Hugging Face's logo

Datasets:
Brizape
/
Variome_split_0404_dev

Modalities:
Text
Formats:
parquet
Size:
1K<n<10K
Tags:
Libraries:
Datasets
pandas
Croissant
Dataset card Viewer Files Community
Dataset Viewer
Auto-converted to Parquet
Viewer
id
stringlengths
22
37
tokens
sequence
ner_tags
sequence
texts
stringlengths
0
39.2k
1619718-05-Discussion-p03
[ "Inactivation", "of", "MLH1", "and", "TP53", "Lynch", "syndrome", "colorectal", "adenomatous", " ", "lesions", "with", "glandular", "serration", "and", "that", "‘traditional’", "SA", "is", "not", "a", "single", "entity." ]
[ 7, 8, 8, 8, 8, 1, 2, 3, 19, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Inactivation of MLH1 and TP53 Lynch syndrome colorectal adenomatous lesions with glandular serration and that ‘traditional’ SA is not a single entity.
3034663-03-Methods-p02
[ "Hardy-Weinberg", "equilibrium", "was", "calculated", "for", "the", "control,", "sporadic", "CRC", "and", "familial", "CRC", "groups.", "Allelic", "and", "genotype", "frequencies", "were", "calculated.", "In", "the", "case-control", "study", "of", "sporadic", "CRC,", "we", "estimated", "the", "odds", "ratio", "(OR)", "and", "95%", "confidence", "interval", "(95%", "CI)", "for", "the", "p.Lys618Ala", "variant", "using", "unconditional", "logistic", "regression", "adjusted", "for", "age", "and", "sex.", "We", "analysed", "for", "potential", "effect", "modification", "by", "age", "using", "an", "analysis", "stratified", "according", "to", "median", "age", "at", "diagnosis", "for", "the", "sporadic", "CRC", "cases", "MLH1", "Tumours", " ", "from", "p.Lys618Ala", "carrier", "cases", "in", "the", "familial", "group", "(seven", "index", "subjects", "and", "one", "relative)", "were", "also", "analysed", "for", "MLH1", "protein", "expression", "using", "immunohistochemistry", "and", "anti-MLH1", "antibodies", "(PharMingen,", "CA,", "USA)", "as", "described", "elsewhere", "[7].", "Tumour", "group", ")", "was", "screened", "for", "MSI", "status", "using", "five", "mononucleotide", "markers", "(BAT26,", "BAT25,", "NR21,", "NR24", "and", "NR27)", "and", "multiplex", "PCR", "as", "previously", "described", "by", "Buhard", "et", "al", "[8]." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 21, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Hardy-Weinberg equilibrium was calculated for the control, sporadic CRC and familial CRC groups. Allelic and genotype frequencies were calculated. In the case-control study of sporadic CRC, we estimated the odds ratio (OR) and 95% confidence interval (95% CI) for the p.Lys618Ala variant using unconditional logistic regression adjusted for age and sex. We analysed for potential effect modification by age using an analysis stratified according to median age at diagnosis for the sporadic CRC cases MLH1 Tumours from p.Lys618Ala carrier cases in the familial group (seven index subjects and one relative) were also analysed for MLH1 protein expression using immunohistochemistry and anti-MLH1 antibodies (PharMingen, CA, USA) as described elsewhere [7]. Tumour group ) was screened for MSI status using five mononucleotide markers (BAT26, BAT25, NR21, NR24 and NR27) and multiplex PCR as previously described by Buhard et al [8].
2275286-04-Results-p02
[ "*Amsterdam", "criteria", "II" ]
[ 0, 0, 0 ]
*Amsterdam criteria II
1557864-03-Methods-p01
[ "Microsatellite", "analysis", "and", "methylation", "specific", "PCR", "(MSP)", "were", "performed", "on", "DNA", "from", "eight", "ovarian", "cancer", "cell", "lines,", "75", "ovarian", "cancer", "specimens", "(part", "of", "a", "collection", "of", "ovarian", "tumor", "specimens", "described", "by", "us", "previously", "[39])", "and", "the", "four", "normal", "stromal", "ovarian", "specimens", "(see", "study", "design", "in", "Figure", "2)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Microsatellite analysis and methylation specific PCR (MSP) were performed on DNA from eight ovarian cancer cell lines, 75 ovarian cancer specimens (part of a collection of ovarian tumor specimens described by us previously [39]) and the four normal stromal ovarian specimens (see study design in Figure 2).
2386495-03-Methods-p01
[ "Patients" ]
[ 0 ]
Patients
1360090-05-Conclusion-p01
[]
[]
3034663-03-Methods-p01
[ "The", "median", "age", "of", "patients", "in", "the", "sporadic", "CRC", "group", "was", "70", "years", "(range,", "52-93", "years),", "47", "years", "(range,", "21-87", "years)", "for", "the", "familial", "group", "and", "71", "years", "(range,", "25-96", "years)", "for", "the", "controls.", "The", "sex", "distribution", "was", "58%", "men", "and", "42%", "women", "for", "the", "sporadic", "CRC", "group", "and", "53.3%", "men", "and", "46.7%", "women", "for", "the", "controls." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The median age of patients in the sporadic CRC group was 70 years (range, 52-93 years), 47 years (range, 21-87 years) for the familial group and 71 years (range, 25-96 years) for the controls. The sex distribution was 58% men and 42% women for the sporadic CRC group and 53.3% men and 46.7% women for the controls.
1619718-05-Discussion-p02
[ "Serrated", "polyps", "with", "dysplasia,", "i.e.", "MPs", "and", "SAs,", "together", "comprised", "only", "2%", "of", "the", "overall", "consecutive", "series", "of", "1250", "polyps.", "While", "mutation", "of", "KRAS", "and", "BRAF", "was", "associated", "with", "conventional", "adenoma", "and", "SSA,", "respectively", "(see", "above),", "BRAF", "and", "KRAS", "mutation", "occurred", "with", "similar", "frequency", "in", "both", "MPs", "(40%", "and", "50%,", "respectively)", "and", "SAs", "(33%", "and", "27%,", "respectively).", "In", "the", "literature,", "the", "frequency", "of", "BRAF", "and", "KRAS", "mutation", "in", "MP", "or", "SA", "has", "ranged", "from", "36", "to", "100%", "and", "from", "0%", "to", "60%,", "respectively.12,16,39–42", "These", "findings", "indicate", "that", "this", "subset", "of", "colorectal", "polyps", "is", "likely", "to", "be", "heterogeneous", "in", "terms", "of", "its", "molecular", "origins.", "These", "polyps", "were", "therefore", "reclassified", "according", "to", "their", "resemblance", "to", "HP", "or", "SSA", "(Group", "A)", "(Figure", "1A,B,E,F)", "or", "to", "conventional", "adenoma", "(Group", "B)", "(Figure", "1C,D).", "Particular", "histological", "features", "among", "the", "Group", "A", "polyps", "were:", "marked", "serration,", "a", "papillary", "or", "villous", "architecture,", "a", "relatively", "abundant", "eosinophilic", "cytoplasm,", "columnar", "cells", "with", "apical", "mucin", "droplets,", "nuclei", "that", "were", "enlarged,", "ovoid,", "vesicular", "and", "contained", "a", "prominent", "nucleolus,", "and", "adjacent", "non-dysplastic", "serrated", "polyp.", "Particular", "histological", "features", "among", "the", "Group", "B", "polyps", "were:", "some", "glandular", "serration,", "frequent", "villous", "change", "and", "epithelial", "dysplasia", "that", "appeared", "adenomatous", "(cytoplasmic", "basophilia", "and", "nuclei", "that", "were", "elongated,", "pseudostratified", "and", "hyperchromatic", "without", "a", "prominent", "nucleolus).", "Importantly,", "BRAF", "epithelial", "dysplasia", "that", "appeared", "adenomatous", " ", "(cytoplasmic", "basophilia", "and", "nuclei", "that", "were", "elongated,", "pseudostratified", "and", "hyperchromatic", "without", "a", "prominent", "nucleolus).", "Importantly,", "BRAF", "mutation", "occurred", "more", "frequently", "among", "Group", "A", "polyps", "(P", "<", "0.03),", "whereas", "there", "was", "a", "trend", "for", "KRAS", " ", "to", "be", "more", "frequent", "among", "Group", "B", "polyps", "mutation", " ", "occurred", "more", "frequently", "among", "Group", "A", "polyps", "conventional", " ", "HPs", "(67%)", "as", "well", "as", "in", "SSAs", "BRAF", " ", "mutation", "in", "conventional", "HPs", "(67%)", "as", "well", "as", "in", "SSAs", "(81%).", "Previous", "reports", "have", "shown", "very", "similar", "results", "for", "BRAF", "mutation", "in", "SSA,16", "but", "higher", "frequencies", "of", "KRAS", "mutation", "and", "lower", "frequencies", "of", "BRAF", "mutation", "in", "HPs.12,16,38", "As", "mentioned", "in", "Materials", "and", "methods,", "there", "had", "been", "selection", "of", "larger", "HPs", "in", "an", "earlier", "cell", "kinetic", "study", "involving", "the", "same", "material.", "Large", "HPs", "are", "more", "likely", "to", "include", "the", "subset", "described", "as", "‘microvesicular’,", "in", "which", "the", "columnar", "cells", "contain", "apical", "mucin", "droplets", "within", "small", "vesicles", "while", "goblet", "cells", "are", "rendered", "inconspicuous.25BRAF", "mutation", "occurs", "more", "frequently", "in", "the", "microvesicular", "variant", "of", "HP.16", "By", "contrast,", "KRAS", "mutation", "occurs", "much", "more", "commonly", "in", "the", "goblet", "cell", "variant", "of", "HP,", "which", "is", "usually", "small,", "located", "in", "the", "left", "colon", "or", "rectum", "and", "deviates", "minimally", "from", "normal", "colorectal", "mucosa", "in", "terms", "of", "differentiation", "and", "architecture.16,25", "The", "latter", "were", "under-represented", "in", "this", "series", "(details", "not", "shown)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, 19, 20, 20, 20, 20, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, 0, 0, 0, 0, 0, 0, 0, 0, 1, 5, 0, 0, 0, 0, 0, 0, 0, 1, 17, 0, 0, 0, 0, 0, 0, 0, 1, 21, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Serrated polyps with dysplasia, i.e. MPs and SAs, together comprised only 2% of the overall consecutive series of 1250 polyps. While mutation of KRAS and BRAF was associated with conventional adenoma and SSA, respectively (see above), BRAF and KRAS mutation occurred with similar frequency in both MPs (40% and 50%, respectively) and SAs (33% and 27%, respectively). In the literature, the frequency of BRAF and KRAS mutation in MP or SA has ranged from 36 to 100% and from 0% to 60%, respectively.12,16,39–42 These findings indicate that this subset of colorectal polyps is likely to be heterogeneous in terms of its molecular origins. These polyps were therefore reclassified according to their resemblance to HP or SSA (Group A) (Figure 1A,B,E,F) or to conventional adenoma (Group B) (Figure 1C,D). Particular histological features among the Group A polyps were: marked serration, a papillary or villous architecture, a relatively abundant eosinophilic cytoplasm, columnar cells with apical mucin droplets, nuclei that were enlarged, ovoid, vesicular and contained a prominent nucleolus, and adjacent non-dysplastic serrated polyp. Particular histological features among the Group B polyps were: some glandular serration, frequent villous change and epithelial dysplasia that appeared adenomatous (cytoplasmic basophilia and nuclei that were elongated, pseudostratified and hyperchromatic without a prominent nucleolus). Importantly, BRAF epithelial dysplasia that appeared adenomatous (cytoplasmic basophilia and nuclei that were elongated, pseudostratified and hyperchromatic without a prominent nucleolus). Importantly, BRAF mutation occurred more frequently among Group A polyps (P < 0.03), whereas there was a trend for KRAS to be more frequent among Group B polyps mutation occurred more frequently among Group A polyps conventional HPs (67%) as well as in SSAs BRAF mutation in conventional HPs (67%) as well as in SSAs (81%). Previous reports have shown very similar results for BRAF mutation in SSA,16 but higher frequencies of KRAS mutation and lower frequencies of BRAF mutation in HPs.12,16,38 As mentioned in Materials and methods, there had been selection of larger HPs in an earlier cell kinetic study involving the same material. Large HPs are more likely to include the subset described as ‘microvesicular’, in which the columnar cells contain apical mucin droplets within small vesicles while goblet cells are rendered inconspicuous.25BRAF mutation occurs more frequently in the microvesicular variant of HP.16 By contrast, KRAS mutation occurs much more commonly in the goblet cell variant of HP, which is usually small, located in the left colon or rectum and deviates minimally from normal colorectal mucosa in terms of differentiation and architecture.16,25 The latter were under-represented in this series (details not shown).
1334229-03-Methods-p01
[ "The", "PALGA", "reports", "were", "used", "to", "identify", "and", "locate", "tumour", "tissue", "from", "eligible", "colorectal", "cancer", "patients", "in", "Dutch", "pathology", "laboratories.", "Colon", "and", "rectal", "cancer", "were", "classified", "according", "to", "site", "as", "follows,", "colon:", "cecum", "through", "sigmoid", "colon", "(ICD-O", "codes", "153.0,", "153.1,", "153.2,", "153.3,", "153.4,", "153.5,", "153.6,", "153.7),", "rectosigmoid", "(ICD-O", "code", "154.0),", "and", "rectum", "(ICD-O", "code", "154.1)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The PALGA reports were used to identify and locate tumour tissue from eligible colorectal cancer patients in Dutch pathology laboratories. Colon and rectal cancer were classified according to site as follows, colon: cecum through sigmoid colon (ICD-O codes 153.0, 153.1, 153.2, 153.3, 153.4, 153.5, 153.6, 153.7), rectosigmoid (ICD-O code 154.0), and rectum (ICD-O code 154.1).
1619718-04-Results-p02
[ "With", "respect", "to", "the", "25", "serrated", "polyps", "with", "dysplasia,", "only", "five", "occurred", "in", "the", "proximal", "colon", "(up", "to", "the", "splenic", "flexure).", "Two", "of", "these", "had", "BRAF", "mutation", "(both", "Group", "A)", "and", "two", "had", "KRAS", "mutation", "(both", "Group", "B).", "Seven", "of", "the", "11", "BRAF", "mutations", "mutation", " ", "(both", "Group", "B).", "Seven", "of", "the", "11", "BRAF", "mutations", "occurred", "in", "polyps", "derived", "from", "the", "left", "colon", " ", "or", "rectum", "BRAF", " ", "mutations", "occurred", "in", "polyps", "polyps", "SAs", "MPs", " ", "and", "SAs", "might", "be", "heterogeneous", "lesions.", "These", "25", "serrated", "polyps", "with", "dysplasia", "mutations", " ", "in", "both", "types", "of", "serrated", "polyp", "indicated", "that", "MPs", "and", "SAs", "might", "be", "heterogeneous", "lesions.", "These", "25", "serrated", "polyps", "with", "dysplasia", "were", "therefore", "grouped", "differently.", "Group", "A", "polyps", "(n", "=", "16)", "included", "a", "non-dysplastic", "serrated", "component", "and/or", "dysplastic", "epithelium", "in", "which", "the", "architectural", "and", "cytological", "changes", "were", "more", "reminiscent", "of", "HP", "than", "adenoma", "(Figure", "1A,B).", "Group", "B", "polyps", "(n", "=", "9)", "comprised", "serrated", "polyps", "in", "which", "the", "epithelial", "dysplasia", "appeared", "adenomatous", "(Figure", "1C,D).", "BRAF", "mutation", "occurred", "in", "10/16", "Group", "A", "polyps", "but", "only", "1/9", "Group", "B", "polyps", "(P", "<", "0.03).", "KRAS", "mutation", "occurred", "in", "only", "3/16", "Group", "A", "polyps", "but", "in", "5/9", "Group", "B", "polyps", "(P", "=", "0.06).", "In", "each", "of", "the", "five", "Group", "B", "polyps", "with", "KRAS", "mutation,", "the", "adenomatous", "component", "showed", "both", "villous", "change", "and", "serration." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 0, 0, 3, 21, 0, 0, 0, 0, 1, 9, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 19, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
With respect to the 25 serrated polyps with dysplasia, only five occurred in the proximal colon (up to the splenic flexure). Two of these had BRAF mutation (both Group A) and two had KRAS mutation (both Group B). Seven of the 11 BRAF mutations mutation (both Group B). Seven of the 11 BRAF mutations occurred in polyps derived from the left colon or rectum BRAF mutations occurred in polyps polyps SAs MPs and SAs might be heterogeneous lesions. These 25 serrated polyps with dysplasia mutations in both types of serrated polyp indicated that MPs and SAs might be heterogeneous lesions. These 25 serrated polyps with dysplasia were therefore grouped differently. Group A polyps (n = 16) included a non-dysplastic serrated component and/or dysplastic epithelium in which the architectural and cytological changes were more reminiscent of HP than adenoma (Figure 1A,B). Group B polyps (n = 9) comprised serrated polyps in which the epithelial dysplasia appeared adenomatous (Figure 1C,D). BRAF mutation occurred in 10/16 Group A polyps but only 1/9 Group B polyps (P < 0.03). KRAS mutation occurred in only 3/16 Group A polyps but in 5/9 Group B polyps (P = 0.06). In each of the five Group B polyps with KRAS mutation, the adenomatous component showed both villous change and serration.
2386495-02-Background-p01
[ "The", "majority", "of", "germline", "APC", "mutations", "identified", "in", "FAP", "families", "cause", "truncations", "in", "this", "multifunctional", "protein", "[6,7].", "The", "APC", "truncations", "most", "often", "occur", "as", "the", "result", "of", "nonsense", "APC", "mutations", "or", "frameshifts", "caused", "by", "small", "deletions/insertions.", "Large", "APC", "deletions", "are", "found", "in", "a", "limited", "number", "of", "FAP", "cases.", "By", "using", "methods", "such", "as", "quantitative", "real-time", "PCR", "(polymerase", "chain", "reaction)", "or", "MLPA", "(multiplex", "ligation-dependent", "probe", "amplification)", "rather", "than", "conventional", "mutation-detection", "techniques,", "we", "can", "achieve", "higher", "detection", "rates", "of", "large", "deletions", "[8-12].", "The", "number", "of", "reported", "characterized", "APC", "splice-site", "mutations", "is", "comparatively", "low", "[13-17].", "Approximately", "10–15%", "of", "the", "FAP", "patients", "could", "have", "a", "reduced", "or", "absent", "APC", "expression", "[18].", "The", "cause", "of", "the", "reduced", "expression", "is", "not", "known", "but", "the", "patients", "show", "a", "similar", "phenotype", "to", "those", "with", "an", "identified", "truncating", "APC", "mutation", "[19-21].", "It", "has", "been", "shown", "that", "a", "decrease", "of", "approximately", "50%", "of", "the", "expression", "of", "an", "allele", "can", "result", "in", "a", "predisposition", "to", "FAP", "[20].", "Germline", "APC-mutation", "mosaicism", "in", "FAP", "patients", "has", "been", "reported", "[22-25]", "but", "is", "not", "generally", "included", "in", "the", "mutation", "screening", "procedure", "provided", "by", "most", "labs", "owing", "to", "the", "technical", "difficulties", "encountered", "with", "these", "analyses." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The majority of germline APC mutations identified in FAP families cause truncations in this multifunctional protein [6,7]. The APC truncations most often occur as the result of nonsense APC mutations or frameshifts caused by small deletions/insertions. Large APC deletions are found in a limited number of FAP cases. By using methods such as quantitative real-time PCR (polymerase chain reaction) or MLPA (multiplex ligation-dependent probe amplification) rather than conventional mutation-detection techniques, we can achieve higher detection rates of large deletions [8-12]. The number of reported characterized APC splice-site mutations is comparatively low [13-17]. Approximately 10–15% of the FAP patients could have a reduced or absent APC expression [18]. The cause of the reduced expression is not known but the patients show a similar phenotype to those with an identified truncating APC mutation [19-21]. It has been shown that a decrease of approximately 50% of the expression of an allele can result in a predisposition to FAP [20]. Germline APC-mutation mosaicism in FAP patients has been reported [22-25] but is not generally included in the mutation screening procedure provided by most labs owing to the technical difficulties encountered with these analyses.
1619718-04-Results-p01
[ "Mutation", "frequencies", "for", "both", "KRAS", "(P", "<", "0.0001)", "and", "BRAF", "(P", "<", "0.0001)", "are", "distributed", "differently", "across", "the", "seven", "classes", "of", "polyp", "(see", "Results", "for", "individual", "comparisons).", "Distribution", "of", "MGMT", "loss", "differs", "across", "the", "seven", "classes", "of", "polyp", "(P", "<", "0.001)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Mutation frequencies for both KRAS (P < 0.0001) and BRAF (P < 0.0001) are distributed differently across the seven classes of polyp (see Results for individual comparisons). Distribution of MGMT loss differs across the seven classes of polyp (P < 0.001).
3034663-03-Methods-p01
[ "The", "median", "age", "of", "patients", "in", "the", "sporadic", "CRC", "group", "was", "70", "years", "(range,", "52-93", "years),", "47", "years", "(range,", "21-87", "years)", "for", "the", "familial", "group", "and", "71", "years", "(range,", "25-96", "years)", "for", "the", "controls.", "The", "sex", "distribution", "was", "58%", "men", "and", "42%", "women", "for", "the", "sporadic", "CRC", "group", "and", "53.3%", "men", "and", "46.7%", "women", "for", "the", "controls." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The median age of patients in the sporadic CRC group was 70 years (range, 52-93 years), 47 years (range, 21-87 years) for the familial group and 71 years (range, 25-96 years) for the controls. The sex distribution was 58% men and 42% women for the sporadic CRC group and 53.3% men and 46.7% women for the controls.
1360090-03-Results-p01
[ "BRAF", "mutations", "showed", "no", "association", "with", "TP53", "mutations", "and", "were", "mutually", "exclusive", "with", "the", "presence", "of", "KRAS", "mutations", "(Table", "2).", "In", "contrast,", "BRAF", "mutations", "were", "approximately", "10-fold", "more", "frequent", "in", "MSI+", "and", "CIMP+", "tumors", "compared", "to", "tumors", "without", "these", "phenotypes.", "A", "strong", "association", "was", "also", "seen", "with", "methylation", "of", "the", "MLH1", "gene", "promoter", "and", "in", "particular", "with", "methylation", "of", "its", "proximal", "region.", "We", "have", "previously", "examined", "the", "methylation", "status", "of", "7", "different", "CpG", "islands", "in", "this", "CRC", "series", "[18].", "The", "mean", "number", "of", "these", "methylated", "sites", "was", "3-fold", "higher", "in", "tumors", "with", "BRAF", "mutation", "compared", "to", "those", "without", "(2.6", "±", "1.7", "vs", "0.8", "±", "1.0;", "P", "<", "0.001).", "Multivariate", "analysis", "revealed", "that", "MSI+", "was", "the", "only", "significant", "independent", "predictor", "of", "BRAF", "mutation", "(RR", "=", "6.3,", "95%CI", "[1.2–32.3];", "P", "=", "0.028)", "in", "a", "model", "that", "included", "CIMP+,", "tumor", "site,", "histological", "grade,", "presence", "of", "infiltrating", "lymphocytes", "and", "mucinous", "appearance." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
BRAF mutations showed no association with TP53 mutations and were mutually exclusive with the presence of KRAS mutations (Table 2). In contrast, BRAF mutations were approximately 10-fold more frequent in MSI+ and CIMP+ tumors compared to tumors without these phenotypes. A strong association was also seen with methylation of the MLH1 gene promoter and in particular with methylation of its proximal region. We have previously examined the methylation status of 7 different CpG islands in this CRC series [18]. The mean number of these methylated sites was 3-fold higher in tumors with BRAF mutation compared to those without (2.6 ± 1.7 vs 0.8 ± 1.0; P < 0.001). Multivariate analysis revealed that MSI+ was the only significant independent predictor of BRAF mutation (RR = 6.3, 95%CI [1.2–32.3]; P = 0.028) in a model that included CIMP+, tumor site, histological grade, presence of infiltrating lymphocytes and mucinous appearance.
2275286-02-Background-p01
[ "MSI", "is", "an", "important", "phenotype", "of", "MMR", "cancer", " ", "[1].", "HNPCC", "patients", "are", "characterized", "by", "earlier", "symptoms,", "more", "mucinous", "more", "mucinous", "carcinoma", ",", "more", "synchronous", "and", "metachronous", "colorectal", "tumors", " ", "and", "more", "extra-colonic", "tumors,", "but", "have", "better", "survival", "[1,2].", "It", "is", "believed", "that", "HNPCC", "is", "secondary", "to", "a", "germline", "mutation", "resulting", "in", "a", "defective", "MMR", "gene.", "A", "defective", "MMR", "gene", "results", "in", "increased", "DNA", "replication", "errors", "and", "MSI,", "which", "causes", "the", "occurrence", "of", "tumors", "in", "different", "organs,", "especially", "in", "the", "colorectum.", "Identification", "of", "HPNCC", "defective", "MMR", "gene", " ", "results", "in", "increased", "DNA", "replication", "errors", "and", "MSI,", "which", "causes", "the", "occurrence", "of", "tumors", "in", "different", "organs,", "especially", "in", "the", "colorectum.", "Identification", "of", "HPNCC", "families", "is", "important", "because", "the", "diagnosis,", "treatment", "and", "follow", "up", "of", "these", "individuals", "should", "be", "different", "from", "those", "with", "sporadic", "colorectal", "cancer", "[2].", "However,", "the", "clinical", "diagnosis", "of", "HNPCC", "patients", "is", "very", "difficult", "for", "lack", "of", "specific", "clinical", "phenotype.", "Though", "Amsterdam", "criteria", "I", "and", "II", "were", "established", "for", "HNPCC", "diagnosis[3,4],", "many", "HNPCC", "families", "still", "do", "not", "meet", "the", "criteria." ]
[ 0, 0, 0, 0, 0, 0, 21, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 19, 20, 20, 0, 17, 18, 18, 18, 18, 18, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 17, 18, 18, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
MSI is an important phenotype of MMR cancer [1]. HNPCC patients are characterized by earlier symptoms, more mucinous more mucinous carcinoma , more synchronous and metachronous colorectal tumors and more extra-colonic tumors, but have better survival [1,2]. It is believed that HNPCC is secondary to a germline mutation resulting in a defective MMR gene. A defective MMR gene results in increased DNA replication errors and MSI, which causes the occurrence of tumors in different organs, especially in the colorectum. Identification of HPNCC defective MMR gene results in increased DNA replication errors and MSI, which causes the occurrence of tumors in different organs, especially in the colorectum. Identification of HPNCC families is important because the diagnosis, treatment and follow up of these individuals should be different from those with sporadic colorectal cancer [2]. However, the clinical diagnosis of HNPCC patients is very difficult for lack of specific clinical phenotype. Though Amsterdam criteria I and II were established for HNPCC diagnosis[3,4], many HNPCC families still do not meet the criteria.
1360090-06-Methods-p01
[ "Statistical", "analyses", "were", "performed", "using", "SPSS", "Version", "12.0", "(Chicago,", "Illinois,", "USA).", "Associations", "between", "BRAF", "mutation", " ", "and", "clinical,", "pathological", "or", "molecular", "features", "were", "evaluated", "using", "Fisher's", "exact", "or", "Pearson's", "chi-squared", "tests", "as", "appropriate.", "Multivariate", "analysis", "was", "performed", "using", "binary", "logistic", "regression", "with", "BRAF", " ", "mutation", " ", "as", "the", "dependent", "variable." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, 0, 5, 0, 0, 0, 0, 0 ]
Statistical analyses were performed using SPSS Version 12.0 (Chicago, Illinois, USA). Associations between BRAF mutation and clinical, pathological or molecular features were evaluated using Fisher's exact or Pearson's chi-squared tests as appropriate. Multivariate analysis was performed using binary logistic regression with BRAF mutation as the dependent variable.
2386495-01-Abstract-p01
[ "Sixty-one", "different", "APC", "mutations", "in", "81", "of", "the", "96", "families", "were", "identified", "and", "27", "of", "those", "are", "novel.", "We", "have", "previously", "shown", "that", "6", "of", "the", "96", "patients", "carried", "biallelic", "MUTYH", "mutations.", "The", "9", "mutation-negative", "cases", "all", "display", "an", "attenuated", "or", "atypical", "phenotype.", "Probands", "with", "a", "genotype", "(codon", "1250–1464)", "predicting", "a", "severe", "phenotype", "had", "a", "median", "age", "at", "diagnosis", "of", "21.8", "(range,", "11–49)", "years", "compared", "with", "34.4", "(range,", "14–57)", "years", "among", "those", "with", "mutations", "outside", "this", "region", "(P", "<", "0.017).", "Dense", "polyposis", "(>", "1000)", "occurred", "in", "75%", "of", "the", "probands", "with", "a", "severe", "phenotype", "compared", "with", "30%", "in", "those", "with", "mutations", "outside", "this", "region.", "The", "morbidity", "in", "colorectal", "cancer", "among", "probands", "was", "25%", "at", "a", "mean", "age", "of", "37.5", "years", "and", "29%", "at", "a", "mean", "age", "of", "46.6", "years." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Sixty-one different APC mutations in 81 of the 96 families were identified and 27 of those are novel. We have previously shown that 6 of the 96 patients carried biallelic MUTYH mutations. The 9 mutation-negative cases all display an attenuated or atypical phenotype. Probands with a genotype (codon 1250–1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11–49) years compared with 34.4 (range, 14–57) years among those with mutations outside this region (P < 0.017). Dense polyposis (> 1000) occurred in 75% of the probands with a severe phenotype compared with 30% in those with mutations outside this region. The morbidity in colorectal cancer among probands was 25% at a mean age of 37.5 years and 29% at a mean age of 46.6 years.
2386495-02-Background-p01
[ "**", "IGNORE", "LINE", "**" ]
[ 0, 0, 0, 0 ]
** IGNORE LINE **
1619718-04-Results-p01
[ "**", "IGNORE", "LINE", "**" ]
[ 0, 0, 0, 0 ]
** IGNORE LINE **
3034663-03-Methods-p01
[ "No", "familial", "history", "of", "cancer", "was", "available", "from", "the", "control", "group.", "Patients", "diagnosed", "at", "an", "age", "over", "50", "years", "and", "not", "referred", "to", "Genetic", "Counselling", "Units", "were", "considered", "as", "sporadic", "CRC.", "Samples", "from", "sporadic", "CRC", "patients", "were", "obtained", "from", "the", "Elche", "University", "Hospital", "BioBank", "and", "the", "Castellon", "Provincial", "Hospital", "BioBank.", "Written", "consent", "to", "be", "included", "in", "the", "respective", "biobanks", "was", "obtained", "from", "each", "patient.", "CRC", "patients,", "as", "index", "subjects", "from", "families", "with", "suspicion", "of", "LS", "that", "attended", "Genetic", "Counselling", "at", "the", "Cancer", "Units", "of", "the", "Elche", "and", "La", "Fe", "Hospitals,", "were", "recruited.", "The", "study", "was", "approved", "by", "the", "Ethics", "Committee", "of", "the", "Elche", "University", "Hospital." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
No familial history of cancer was available from the control group. Patients diagnosed at an age over 50 years and not referred to Genetic Counselling Units were considered as sporadic CRC. Samples from sporadic CRC patients were obtained from the Elche University Hospital BioBank and the Castellon Provincial Hospital BioBank. Written consent to be included in the respective biobanks was obtained from each patient. CRC patients, as index subjects from families with suspicion of LS that attended Genetic Counselling at the Cancer Units of the Elche and La Fe Hospitals, were recruited. The study was approved by the Ethics Committee of the Elche University Hospital.
2275286-01-Abstract-p01
[ "Methods" ]
[ 0 ]
Methods
1619718-05-Discussion-p03
[ "Colorectal", "polyps", "have", "traditionally", "been", "classified", "into", "distinct", "histogenetic", "types", "that", "may", "progress", "to", "CRC", "through", "independent", "pathways", "of", "colorectal", "tumorigenesis", "(Table", "2).", "However,", "in", "addition", "to", "the", "two", "‘classical’", "pathways", "to", "CRC", "shown", "in", "Table", "2,", "there", "may", "be", "‘fusion’", "pathways", "that", "combine", "mechanisms", "associated", "with", "both", "adenomas", "and", "serrated", "polyps.", "This", "would", "explain", "why", "many", "CRCs", "display", "phenotypes", "associated", "with", "serrated", "polyps", "as", "well", "as", "adenomas.44", "Three", "possible", "examples", "of", "such", "fusion", "pathways", "are", "shown", "in", "Table", "3.", "It", "is", "difficult", "to", "observe", "directly", "the", "actual", "point", "of", "transition", "from", "benign", "to", "malignant", " ", "colorectal", "lesions.", "Once", "the", "key", "rate-limiting", "step", "is", "achieved", "it", "is", "likely", "that", "the", "transition", "to", "cancer", "occurs", "rapidly", "and", "the", "precursor", "SA", " ", "is", "not", "a", "single", "entity." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 17, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 17, 1, 0, 0, 0, 0, 0, 0 ]
Colorectal polyps have traditionally been classified into distinct histogenetic types that may progress to CRC through independent pathways of colorectal tumorigenesis (Table 2). However, in addition to the two ‘classical’ pathways to CRC shown in Table 2, there may be ‘fusion’ pathways that combine mechanisms associated with both adenomas and serrated polyps. This would explain why many CRCs display phenotypes associated with serrated polyps as well as adenomas.44 Three possible examples of such fusion pathways are shown in Table 3. It is difficult to observe directly the actual point of transition from benign to malignant colorectal lesions. Once the key rate-limiting step is achieved it is likely that the transition to cancer occurs rapidly and the precursor SA is not a single entity.
2386495-03-Methods-p02
[ "Analyses", "of", "APC", "expression" ]
[ 0, 0, 0, 0 ]
Analyses of APC expression
2275286-04-Results-p02
[ "Clinical", "features", "of", "patients", "in", "MSI", "group", "with", "MMR", "gene", "mutations" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Clinical features of patients in MSI group with MMR gene mutations
1619718-05-Discussion-p03
[ "Colorectal", "polyps", "have", "traditionally", "been", "classified", "into", "distinct", "histogenetic", "types", "that", "may", "progress", "to", "CRC", "through", "independent", "pathways", "of", "colorectal", "tumorigenesis", "(Table", "2).", "However,", "in", "addition", "to", "the", "two", "‘classical’", "pathways", "to", "CRC", "shown", "in", "Table", "2,", "there", "may", "be", "‘fusion’", "pathways", "that", "combine", "mechanisms", "associated", "with", "both", "adenomas", "and", "serrated", "polyps.", "This", "would", "explain", "why", "many", "CRCs", "display", "phenotypes", "associated", "with", "serrated", "polyps", "as", "well", "as", "adenomas.44", "Three", "possible", "examples", "of", "such", "fusion", "pathways", "are", "shown", "in", "Table", "3.", "It", "is", "difficult", "to", "observe", "directly", "the", "actual", "point", "of", "transition", "from", "benign", "to", "malignant", "colorectal", "lesions.", "Once", "the", "key", "rate-limiting", "step", "is", "achieved", "it", "is", "likely", "that", "the", "transition", "to", "cancer", "occurs", "rapidly", "and", "the", "precursor", "lesion", "is", "then", "overtaken", "by", "the", "malignancy.", "Changes", "leading", "to", "inactivation", "of", "either", "TP535", "or", "the", "DNA", "mismatch", "repair", "gene", "MLH113", "are", "likely", "to", "be", "two", "such", "rate-limiting", "mechanisms.", "Only", "a", "single", "instance", "of", "loss", "of", "expression", "of", "MLH1", "was", "observed", "in", "the", "present", "series", "of", "polyps", "and", "the", "adenoma", "in", "question", "was", "inferred", "to", "be", "from", "a", "patient", "with", "Lynch", "syndrome.24" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Colorectal polyps have traditionally been classified into distinct histogenetic types that may progress to CRC through independent pathways of colorectal tumorigenesis (Table 2). However, in addition to the two ‘classical’ pathways to CRC shown in Table 2, there may be ‘fusion’ pathways that combine mechanisms associated with both adenomas and serrated polyps. This would explain why many CRCs display phenotypes associated with serrated polyps as well as adenomas.44 Three possible examples of such fusion pathways are shown in Table 3. It is difficult to observe directly the actual point of transition from benign to malignant colorectal lesions. Once the key rate-limiting step is achieved it is likely that the transition to cancer occurs rapidly and the precursor lesion is then overtaken by the malignancy. Changes leading to inactivation of either TP535 or the DNA mismatch repair gene MLH113 are likely to be two such rate-limiting mechanisms. Only a single instance of loss of expression of MLH1 was observed in the present series of polyps and the adenoma in question was inferred to be from a patient with Lynch syndrome.24
1601966-03-Results-p02
[ "Whole-chromosome", "plots", "of", "running", "average", "of", "fractions", "of", "samples", "showing", "up-/down-regulation", "in", "tumor", "versus", "normal", "samples", "(Chromosomes", "5,", "6,", "7,", "8,", "9,", "10).", "For", "each", "chromosome", "you", "see", "a", "separate", "figure.", "Gray", "dots", "denote", "the", "number", "of", "patients", "with", "up-", "or", "down-regulation", "for", "a", "single", "gene.", "Orange/green", "lines", "represent", "a", "running", "average", "of", "these", "values.", "The", "plots", "are", "made", "to", "be", "easily", "comparable", "with", "whole-genome", "CGH", "plots", "(like", "e.g.", "those", "in", "Knösel", "et", "al.", "[21])", "Further", "details", "of", "plot", "construction", "are", "described", "in", "the", "methods", "section." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Whole-chromosome plots of running average of fractions of samples showing up-/down-regulation in tumor versus normal samples (Chromosomes 5, 6, 7, 8, 9, 10). For each chromosome you see a separate figure. Gray dots denote the number of patients with up- or down-regulation for a single gene. Orange/green lines represent a running average of these values. The plots are made to be easily comparable with whole-genome CGH plots (like e.g. those in Knösel et al. [21]) Further details of plot construction are described in the methods section.
1557864-05-Discussion-p02
[ "Since", "ovarian", "cancer", "ovarian", " ", "carcinomas", "to", "determine", "the", "frequency", "of", "MMR", "inactivation", "in", "ovarian", "cancer", "in", "vivo.", "Seven", "of", "the", "75", "ovarian", "carcinomas", "showed", "MLH1", "promoter", "methylation.", "We", "confirmed", "whether", "the", "observed", "MLH1", "promoter", "methylation", "results", "in", "the", "inactivation", "of", "the", "gene", "by", "determining", "the", "MLH1", "mRNA", "expression", "with", "quantitative", "RT-PCR.", "The", "six", "tumors", "with", "low", "level", "MLH1", "promoter", "methylation", "appeared", "to", "express", "MLH1", "at", "mRNA", "levels", "similar", "to", "that", "of", "the", "unmethylated", "tumors.", "Thus", "a", "low", "level", "of", "methylation", "does", "not", "result", "in", "an", "altered", "expression", "of", "the", "MLH1", "gene.", "In", "contrast,", "the", "abundant", "methylation", "seen", "in", "the", "remaining", "carcinoma", "was", "associated", "with", "the", "lowest", "MLH1", "mRNA", "expression", "level", "of", "all", "50", "ovarian", " ", "cancer", "in", "vivo.", "Seven", "of", "the", "75", "ovarian", " ", "carcinomas", "showed", "MLH1", "promoter", "methylation.", "We", "confirmed", "whether", "the", "observed", "MLH1", "promoter", "methylation", "results", "in", "the", "inactivation", "of", "the", "gene", "by", "determining", "the", "MLH1", "mRNA", "expression", "with", "quantitative", "RT-PCR.", "The", "six", "tumors", "with", "low", "level", "MLH1", "promoter", "methylation", "appeared", "to", "express", "MLH1", "at", "mRNA", "levels", "similar", "to", "that", "of", "the", "unmethylated", "tumors.", "Thus", "a", "low", "level", "of", "methylation", "does", "not", "result", "in", "an", "altered", "expression", "of", "the", "MLH1", "gene.", "In", "contrast,", "the", "abundant", "methylation", "seen", "in", "the", "remaining", "carcinoma", "was", "associated", "with", "the", "lowest", "MLH1", "mRNA", "expression", "level", "of", "all", "50", "ovarian", "carcinomas", "tested.", "However,", "none", "of", "the", "ovarian", "carcinomas", "showed", "MSI", "for", "BAT25,", "BAT26", "and", "for", "BAT40", "or", "D2S123", "which", "suggests", "a", "frequency", "of", "MMR", "inactivation", "of", "0%.", "The", "low", "MLH1", "mRNA", "expression", "seen", "in", "the", "abundant", "methylated", "carcinoma", "might", "be", "sufficient", "enough", "for", "a", "functional", "MMR", "which", "results", "in", "the", "observed", "absence", "of", "MSI." ]
[ 0, 1, 2, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 3, 0, 0, 0, 0, 0, 0, 0, 0, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Since ovarian cancer ovarian carcinomas to determine the frequency of MMR inactivation in ovarian cancer in vivo. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation. We confirmed whether the observed MLH1 promoter methylation results in the inactivation of the gene by determining the MLH1 mRNA expression with quantitative RT-PCR. The six tumors with low level MLH1 promoter methylation appeared to express MLH1 at mRNA levels similar to that of the unmethylated tumors. Thus a low level of methylation does not result in an altered expression of the MLH1 gene. In contrast, the abundant methylation seen in the remaining carcinoma was associated with the lowest MLH1 mRNA expression level of all 50 ovarian cancer in vivo. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation. We confirmed whether the observed MLH1 promoter methylation results in the inactivation of the gene by determining the MLH1 mRNA expression with quantitative RT-PCR. The six tumors with low level MLH1 promoter methylation appeared to express MLH1 at mRNA levels similar to that of the unmethylated tumors. Thus a low level of methylation does not result in an altered expression of the MLH1 gene. In contrast, the abundant methylation seen in the remaining carcinoma was associated with the lowest MLH1 mRNA expression level of all 50 ovarian carcinomas tested. However, none of the ovarian carcinomas showed MSI for BAT25, BAT26 and for BAT40 or D2S123 which suggests a frequency of MMR inactivation of 0%. The low MLH1 mRNA expression seen in the abundant methylated carcinoma might be sufficient enough for a functional MMR which results in the observed absence of MSI.
1360090-03-Results-p01
[ "(A)", "Representative", "F-SSCP", "gel", "used", "to", "detect", "BRAF", "mutationsin", "colorectal", "cancer.", "WT,", "wild-type;", "M,", "mutation.", "(B)", "DNA", "sequencing", "gel", "resultconfirms", "the", "presence", "of", "a", "1799T", "to", "A", "mutation", "giving", "rise", "to", "the", "V600E", "mutation." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
(A) Representative F-SSCP gel used to detect BRAF mutationsin colorectal cancer. WT, wild-type; M, mutation. (B) DNA sequencing gel resultconfirms the presence of a 1799T to A mutation giving rise to the V600E mutation.
1334229-05-Discussion-p02
[ "The", "K-ras", "mutation", "frequency", "of", "37%", "is", "in", "accordance", "with", "reported", "frequencies", "of", "30", "to", "60%", "[33-43].", "The", "frequency", "of", "37%", "of", "truncating", "mutations", "in", "the", "mutation", "cluster", "region", "of", "APC", "in", "this", "study,", "however,", "seems", "low", "in", "comparison", "to", "the", "general", "assumption", "that", "most", "colorectal", "tumours", "harbour", "a", "mutation", "in", "the", "APC", "gene.", "When", "only", "reports", "from", "studies", "on", "sporadic", "rather", "than", "familial", "colorectal", "cancer", "or", "colorectal", "cancer", "cell", "lines", "are", "considered,", "the", "mutation", "frequencies", "are", "lower", "and", "vary", "between", "30", "and", "70%", "[17,44-49],", "and", "a", "population-based", "case-control", "study", "in", "the", "Netherlands", "reported", "a", "32%", "mutation", "frequency", "[50]." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The K-ras mutation frequency of 37% is in accordance with reported frequencies of 30 to 60% [33-43]. The frequency of 37% of truncating mutations in the mutation cluster region of APC in this study, however, seems low in comparison to the general assumption that most colorectal tumours harbour a mutation in the APC gene. When only reports from studies on sporadic rather than familial colorectal cancer or colorectal cancer cell lines are considered, the mutation frequencies are lower and vary between 30 and 70% [17,44-49], and a population-based case-control study in the Netherlands reported a 32% mutation frequency [50].
1373649-03-Methods-p02
[ "A", "second", "blood", "sample", "was", "obtained", "from", "the", "proband's", "mother", "and", "forwarded", "to", "the", "Department", "of", "Clinical", "Cancer", "Genetics", "(City", "of", "Hope", "Cancer", "Center,", "Duarte,", "California,", "USA)", "to", "full", "mutation", "analysis", "of", "the", "hMSH2", "and", "hMLH1", "genes.", "The", "sample", "was", "amplified", "followed", "by", "direct", "sequencing", "to", "screen", "the", "coding", "regions", "of", "both", "the", "hMSH2", "and", "the", "hMLH1", "genes", "for", "germline", "mutation", "in", "the", "DNA." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
A second blood sample was obtained from the proband's mother and forwarded to the Department of Clinical Cancer Genetics (City of Hope Cancer Center, Duarte, California, USA) to full mutation analysis of the hMSH2 and hMLH1 genes. The sample was amplified followed by direct sequencing to screen the coding regions of both the hMSH2 and the hMLH1 genes for germline mutation in the DNA.
2275286-04-Results-p02
[ "*Amsterdam", "criteria", "II" ]
[ 0, 0, 0 ]
*Amsterdam criteria II
1601966-03-Results-p02
[ "**", "IGNORE", "LINE", "**" ]
[ 0, 0, 0, 0 ]
** IGNORE LINE **
2386495-04-Results-p02
[ "Three", "patients", "(C107,", "C257,", "and", "C505),", "negative", "for", "mutations", "in", "APC,", "were", "reported", "as", "de", "novo", "cases", "with", "no", "known", "family", "history", "of", "FAP", "exons", "13", "through", "the", "5'", "part", "of", "exon", "15", ",", "was", "carried", "out", "with", "MLPA.", "The", "deletion", "in", "patient", "2136", "was", "identified", "by", "PTT", "and", "subsequent", "DNA", "sequencing." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 17, 18, 18, 18, 18, 18, 5, 6, 6, 6, 6, 6, 6, 6, 6, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Three patients (C107, C257, and C505), negative for mutations in APC, were reported as de novo cases with no known family history of FAP exons 13 through the 5' part of exon 15 , was carried out with MLPA. The deletion in patient 2136 was identified by PTT and subsequent DNA sequencing.
2275286-01-Abstract-p01
[ "Our", "data", "may", "imply", "that", "the", "characteristics", "of", "HNPCC", "in", "the", "Chinese", "population", "are", "probably", "different", "from", "those", "of", "Western", "countries.", "Application", "of", "NCI", "recommended", "criteria", "may", "not", "be", "effective", "enough", "to", "identify", "Chinese", "MSI", " ", "CRCs.", "Hypermethylation", "of", "the", "MLH1", "promoter", "occurred", "in", "14", "(73.7%)", "out", "of", "19", "MSI-H", "CRCs", "and", "5", "(33.3%)", "out", "of", "15", "MSI-L", "CRCs.", "Among", "the", "34", "MSI", "carriers", "and", "one", "MSS", "CRC", "with", "MLH1", "negative", "staining,", "8", "MLH1", "promoter", "methylation", "germline", "mutation", " ", "carriers", "among", "a", "Chinese", "population", "with", "colorectal", "cancer." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 25, 19, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 7, 8, 8, 5, 6, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Our data may imply that the characteristics of HNPCC in the Chinese population are probably different from those of Western countries. Application of NCI recommended criteria may not be effective enough to identify Chinese MSI CRCs. Hypermethylation of the MLH1 promoter occurred in 14 (73.7%) out of 19 MSI-H CRCs and 5 (33.3%) out of 15 MSI-L CRCs. Among the 34 MSI carriers and one MSS CRC with MLH1 negative staining, 8 MLH1 promoter methylation germline mutation carriers among a Chinese population with colorectal cancer.
2386495-05-Discussion-p04
[ "The", "61", "different", "APC", "mutations", "listed", "in", "Additional", "file", "2", "were", "identified", "among", "81", "of", "the", "96", "family", " ", "includes", "150", "individuals", "of", "whom", "57", "are", "affected", "by", "the", "disease", "(Figure", "6", "shows", "part", "of", "the", "pedigree).", "However,", "no", "pathogenic", "mutation", "had", "been", "detected", "after", "screening", "the", "whole", "coding", "region", "of", "the", "APC", "gene", "but", "as", "the", "family", "did", "show", "positive", "linkage", "to", "the", "APC", "locus", "we", "decided", "to", "perform", "expression", "analyses", "and", "evidence", "of", "lowered", "APC", "expression", "was", "obtained", "by", "quantitative", "real-time", "PCR", "(Figure", "5A).", "The", "result", "was", "supported", "by", "the", "indication", "of", "a", "lower", "expression", "from", "the", "T-allele", "from", "analysis", "of", "the", "APC", "c.5465A", ">", "T", "polymorphism", "in", "the", "cDNA", "sequencing", "diagram", "of", "two", "affected", "family", "members", "(Figure", "5B).", "The", "search", "for", "mutations", "in", "the", "DNA", "sequence", "of", "the", "APC", "promoters", "has", "been", "initiated,", "but", "no", "pathogenic", "change", "has", "been", "detected", "to", "this", "date.", "The", "possibility", "of", "the", "pathogenic", "change", "being", "epigenetic", "will", "have", "to", "be", "investigated", "further.", "Hypermethylation", "of", "CpG", "sites", "in", "the", "promoter", "of", "APC", "has", "been", "reported", "as", "a", "means", "of", "gene", "silencing", "in", "colorectal", "tumors", "[46-49].", "To", "the", "best", "of", "the", "authors'", "knowledge", "no", "germ-line", "inactivation", "of", "APC", "caused", "by", "promoter", "hypermethylation", "has", "been", "reported.", "However,", "cases", "of", "pathogenic", "germline", "epimutations", "have", "been", "identified", "in", "the", "MLH1", "gene,", "which", "causes", "hereditary", "non-polyposis", "CRC", "[50,51]." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 12, 12, 12, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The 61 different APC mutations listed in Additional file 2 were identified among 81 of the 96 family includes 150 individuals of whom 57 are affected by the disease (Figure 6 shows part of the pedigree). However, no pathogenic mutation had been detected after screening the whole coding region of the APC gene but as the family did show positive linkage to the APC locus we decided to perform expression analyses and evidence of lowered APC expression was obtained by quantitative real-time PCR (Figure 5A). The result was supported by the indication of a lower expression from the T-allele from analysis of the APC c.5465A > T polymorphism in the cDNA sequencing diagram of two affected family members (Figure 5B). The search for mutations in the DNA sequence of the APC promoters has been initiated, but no pathogenic change has been detected to this date. The possibility of the pathogenic change being epigenetic will have to be investigated further. Hypermethylation of CpG sites in the promoter of APC has been reported as a means of gene silencing in colorectal tumors [46-49]. To the best of the authors' knowledge no germ-line inactivation of APC caused by promoter hypermethylation has been reported. However, cases of pathogenic germline epimutations have been identified in the MLH1 gene, which causes hereditary non-polyposis CRC [50,51].
1266026-04-Results-p01
[ "Ages", "at", "cancer", "can", "be", "used", "to", "estimate", "likely", "numbers", "of", "oncogenic", "mutations", "required", "before", "transformation", "[3-6,11].", "Average", "ages", "for", "sporadic", "MSI+,", "MSI-,", "and", "HNPCC", "cancers", "were", "respectively", "71.5,", "67.5,", "and", "50.3", "years", "(Figure", "1A).", "For", "HNPCC", "cancers,", "estimated", "numbers", "of", "oncogenic", "mutations", "were", "between", "four", "and", "seven", "(95%", "credibility", "interval),", "with", "the", "most", "likely", "value", "of", "five", "mutations", "(Table", "1).", "For", "MSI+", "sporadic", "cancers,", "estimated", "numbers", "of", "mutations", "were", "between", "six", "and", "nine", "(95%", "credibility", "interval)", "with", "more", "likely", "values", "of", "seven", "or", "eight", "mutations.", "The", "most", "likely", "number", "of", "mutations", "was", "seven", "for", "sporadic", "MSI-", "cancers." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Ages at cancer can be used to estimate likely numbers of oncogenic mutations required before transformation [3-6,11]. Average ages for sporadic MSI+, MSI-, and HNPCC cancers were respectively 71.5, 67.5, and 50.3 years (Figure 1A). For HNPCC cancers, estimated numbers of oncogenic mutations were between four and seven (95% credibility interval), with the most likely value of five mutations (Table 1). For MSI+ sporadic cancers, estimated numbers of mutations were between six and nine (95% credibility interval) with more likely values of seven or eight mutations. The most likely number of mutations was seven for sporadic MSI- cancers.
3034663-02-Background-p01
[ "Background" ]
[ 0 ]
Background
3034663-04-Results-p01
[ "In", "the", "second", "LS", "family,", "the", "index", "subject,", "one", "sister", "and", "one", "brother", "with", "CRC", "(II-5;", "II-6;", "II-7,", "respectively)", "had", "a", "deleterious", "variant", "in", "MSH6", "(c.3013C>T;", "p.Arg1005X)", "but", "did", "not", "have", "the", "p.Lys618Ala", "variant.", "This", "variant", "was", "present", "in", "only", "three", "of", "four", "unaffected", "nephews", "(", "III-2", "c.767C>T", "index", "subject", " ", "was", "heterozygous", "for", "a", "pathogenic", "MLH1", "variant", "(c.767C>T;", "p.Arg226X)", "and", "the", "p.Lys618Ala", "variant.", "Two", "of", "his", "offspring,", "who", "were", "diagnosed", "with", "CRC", "at", "the", "ages", "of", "36", "and", "39", "years,", "carried", "the", "deleterious", "variant", "but", "not", "the", "p.Lys618Ala", "variant.", "An", "unaffected", "daughter", "(III-12)", "carried", "the", "p.Lys618Ala", "variant", "but", "not", "the", "deleterious", "variant.", "Two", "nephews", "(III-3;", "III-4)", "were", "also", "diagnosed", "with", "CRC", "at", "the", "ages", "of", "30", "and", "42", "years", "and", "they", "carried", "only", "the", "deleterious", "variant.", "Two", "other", "healthy", "nephews", "(III-6;", "III-7)", "had", "the", "wild", "types", "of", "the", "two", "variants", "(Family", "#1,", "Figure", "2)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 5, 9, 10, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
In the second LS family, the index subject, one sister and one brother with CRC (II-5; II-6; II-7, respectively) had a deleterious variant in MSH6 (c.3013C>T; p.Arg1005X) but did not have the p.Lys618Ala variant. This variant was present in only three of four unaffected nephews ( III-2 c.767C>T index subject was heterozygous for a pathogenic MLH1 variant (c.767C>T; p.Arg226X) and the p.Lys618Ala variant. Two of his offspring, who were diagnosed with CRC at the ages of 36 and 39 years, carried the deleterious variant but not the p.Lys618Ala variant. An unaffected daughter (III-12) carried the p.Lys618Ala variant but not the deleterious variant. Two nephews (III-3; III-4) were also diagnosed with CRC at the ages of 30 and 42 years and they carried only the deleterious variant. Two other healthy nephews (III-6; III-7) had the wild types of the two variants (Family #1, Figure 2).
2275286-04-Results-p02
[ "MSI", "state,", "germline", "mutations,", "and", "consequential", "changes", "in", "amino-acid", "sequence" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
MSI state, germline mutations, and consequential changes in amino-acid sequence
2386495-03-Methods-p01
[ "Age,", "age", "at", "diagnosis;", "DL,", "duodenal", "lesion;", "dom,", "dominant;", "FGP,", "fundic", "gland", "polyps;", "NA,", "no", "available", "data;", "NI,", "no", "inheritance;", "Number", "of", "polyps,", "number", "of", "polyps", "at", "diagnosis;", "rec,", "recessive" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Age, age at diagnosis; DL, duodenal lesion; dom, dominant; FGP, fundic gland polyps; NA, no available data; NI, no inheritance; Number of polyps, number of polyps at diagnosis; rec, recessive
3034663-05-Discussion-p01
[ "Classification", "of", "the", "MLH1", "p.Lys618Ala", "variant", "according", "to", "the", "InSiGHT", "database", "(accessed", "on", "07/2010)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Classification of the MLH1 p.Lys618Ala variant according to the InSiGHT database (accessed on 07/2010).
1334229-02-Background-p01
[ "Genetic", "instability", "is", "seen", "in", "most", "types", "of", "cancer", "[10].", "Two", "distinct", "types", "of", "genetic", "instability", "appear", "to", "occur", "in", "colorectal", "cancer", "[11]:", "chromosomal", "and", "microsatellite", "instability.", "Chromosomal", "instability", "results", "in", "gains", "or", "losses", "of", "entire", "chromosomes", "or", "parts", "of", "them,", "and", "gives", "rise", "to", "aneuploid", " ", "tumours", "and", "occurs", "in", "the", "majority", "of", "cancers.", "A", "smaller", "proportion", "of", "colorectal", "cancers", "displays", "microsatellite", "instability,", "represented", "by", "diploid", "cells", "acquiring", "high", "mutation", "rates,", "and", "was", "found", "to", "be", "associated", "with", "defective", "mismatch", "repair", "[12].", "These", "tumours", "are", "less", "likely", "to", "harbour", "mutations", "in", "genes", "associated", "with", "chromosomally", "instable", "and", "generally", "aneuploid", "tumours,", "such", "as", "APC,", "K-ras", "and", "TP53", "[13-21],", "suggesting", "that", "these", "tumours", "form", "a", "distinct", "group.", "Moreover,", "microsatellite", "instable", "tumours", "are", "found", "predominantly", "in", "the", "proximal", "colon", "carcinogenesis", "colorectal", ")", "carcinogenesis", "[2].", "A", "genetic", "model", "for", "sporadic", "colorectal", "cancer", "has", "been", "proposed,", "which", "describes", "the", "sequential", "accumulation", "of", "specific", "genetic", "alterations", "in", "various", "pathways,", "involving", "tumour", "suppressor", "genes", "(e.g.", "APC,", "SMAD4,", "TP53)", "and", "oncogenes", "(e.g.", "CTNNB1,", "K-ras)", "[3,4].", "Important", "molecular", "pathways", "that", "upon", "activation", "affect", "the", "early", "and", "intermediate", "stages", "of", "colorectal", "carcinogenesis", "are", "the", "Wnt", "and", "Ras", "signalling", "pathways,", "whereas", "TP53", "inactivation", "is", "considered", "a", "late", "event." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 1, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Genetic instability is seen in most types of cancer [10]. Two distinct types of genetic instability appear to occur in colorectal cancer [11]: chromosomal and microsatellite instability. Chromosomal instability results in gains or losses of entire chromosomes or parts of them, and gives rise to aneuploid tumours and occurs in the majority of cancers. A smaller proportion of colorectal cancers displays microsatellite instability, represented by diploid cells acquiring high mutation rates, and was found to be associated with defective mismatch repair [12]. These tumours are less likely to harbour mutations in genes associated with chromosomally instable and generally aneuploid tumours, such as APC, K-ras and TP53 [13-21], suggesting that these tumours form a distinct group. Moreover, microsatellite instable tumours are found predominantly in the proximal colon carcinogenesis colorectal ) carcinogenesis [2]. A genetic model for sporadic colorectal cancer has been proposed, which describes the sequential accumulation of specific genetic alterations in various pathways, involving tumour suppressor genes (e.g. APC, SMAD4, TP53) and oncogenes (e.g. CTNNB1, K-ras) [3,4]. Important molecular pathways that upon activation affect the early and intermediate stages of colorectal carcinogenesis are the Wnt and Ras signalling pathways, whereas TP53 inactivation is considered a late event.
3034663-05-Discussion-p01
[ "LS", "is", "the", "most", "common", "hereditary", "CRC-predisposing", "syndrome", "and", "accounts", "for", "3%", "of", "unselected", "CRC", "cases.", "A", "significant", "proportion", "of", "DNA", "variations", "found", "in", "patients", "suspected", "of", "having", "LS", "are", "UVs", "(32%,", "18%", "and", "38%", "for", "MLH1,", "MSH2", "and", "MSH6,", "respectively)", "[6].", "The", "pathogenicity", "of", "the", "MLH1", "p.Lys618Ala", "variant", "remains", "controversial", "because", "of", "conflicting", "data", "[InSiGHT,", "http://www.insight-group.org]", "(Figure", "5)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
LS is the most common hereditary CRC-predisposing syndrome and accounts for 3% of unselected CRC cases. A significant proportion of DNA variations found in patients suspected of having LS are UVs (32%, 18% and 38% for MLH1, MSH2 and MSH6, respectively) [6]. The pathogenicity of the MLH1 p.Lys618Ala variant remains controversial because of conflicting data [InSiGHT, http://www.insight-group.org] (Figure 5).
2275286-04-Results-p02
[ "P", "=", "0.112" ]
[ 0, 0, 0 ]
P = 0.112
1601966-03-Results-p10
[ "Down-regulation", "of", "mRNA", "expression", "in", "human", "chromosomal", "region", "18q21.2-18q23", "–", "the", "BCL2", "region", "(patient", "counts", "with", "coordinate", "up-regulation).", "Grayscale", "cross-comparison", "plot", "of", "up-regulation", "patterns", "across", "patients", "(analogous", "to", "Figures", "7,", "10,", "13).", "View", "this", "plot", "in", "conjunction", "with", "Figures", "24", "and", "26." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Down-regulation of mRNA expression in human chromosomal region 18q21.2-18q23 – the BCL2 region (patient counts with coordinate up-regulation). Grayscale cross-comparison plot of up-regulation patterns across patients (analogous to Figures 7, 10, 13). View this plot in conjunction with Figures 24 and 26.
1360090-03-Results-p01
[ "Associations", "between", "BRAF", "mutation", "and", "clinicopathological", "features", "of", "colorectal", "cancer." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Associations between BRAF mutation and clinicopathological features of colorectal cancer.
1601966-03-Results-p11
[ "The", "chromosomal", "region", "14q24.3", "has", "been", "implicated", "in", "colorectal", "cancer", "several", "times", "(see", "Table", "1).", "We", "found", "coordinated", "down-regulation", "of", "expression", "of", "genes", "in", "14q24.1-14q24.3", "(see", "Figures", "30,", "31,", "32).", "The", "region", "comprises", "the", "MLH3", "gene", "that", "is", "linked", "to", "hereditary", "non-polyposis", "colorectal", "cancer", "type", "7", "(HNPCC7).", "We", "note", "that", "also", "the", "FOS", "gene", "encoding", "one", "half", "of", "the", "bZIP", "dimer", "activator", "protein", "(AP-1)", "at", "14q24.3", "is", "strongly", "down-regulated.", "FOS", "is", "known", "as", "an", "oncogene", "and", "its", "down-regulation", "is", "therefore", "unexpected.", "However,", "deletions", "of", "14q24.3", "have", "been", "linked", "to", "metastatic", "CRC", "TIGA1", "colon", "cancer", " ", "(see", "Table", "4).", "APC", "itself", "is", "not", "represented", "in", "this", "plot", "(no", "valid", "expression", "measures).", "It", "is", "located", "down-stream", "of", "TIGA1", "and", "up-stream", "of", "DP1", "and", "DCP2.", "Note", "the", "sharp", "change", "from", "expression", "up-regulation", "(TIGA1)", "to", "expression", "down-regulation", "(DCP2", "to", "DMXL1)", "in", "this", "interval." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 21, 1, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The chromosomal region 14q24.3 has been implicated in colorectal cancer several times (see Table 1). We found coordinated down-regulation of expression of genes in 14q24.1-14q24.3 (see Figures 30, 31, 32). The region comprises the MLH3 gene that is linked to hereditary non-polyposis colorectal cancer type 7 (HNPCC7). We note that also the FOS gene encoding one half of the bZIP dimer activator protein (AP-1) at 14q24.3 is strongly down-regulated. FOS is known as an oncogene and its down-regulation is therefore unexpected. However, deletions of 14q24.3 have been linked to metastatic CRC TIGA1 colon cancer (see Table 4). APC itself is not represented in this plot (no valid expression measures). It is located down-stream of TIGA1 and up-stream of DP1 and DCP2. Note the sharp change from expression up-regulation (TIGA1) to expression down-regulation (DCP2 to DMXL1) in this interval.
2386495-03-Methods-p01
[ "Patients", "without", "any", "detected", "mutation", "in", "APC", "or", "MUTYH" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Patients without any detected mutation in APC or MUTYH
1334229-03-Methods-p02
[ "The", "majority", "of", "somatic", "mutations", "in", "the", "APC", "gene", "are", "found", "within", "the", "mutation", "cluster", "region", "(codons", "1286–1520).", "Mutation", "analysis", "of", "the", "mutation", "cluster", "region", "was", "performed", "on", "adenocarcinoma", "DNA", "using", "nested", "PCR", "for", "amplification", "of", "the", "mutation", "cluster", "region", "as", "four", "overlapping", "DNA", "fragments", "followed", "by", "direct", "sequencing", "of", "purified", "fragments,", "as", "previously", "described", "[28].", "An", "alternative", "nested", "PCR", "strategy", "was", "performed", "when", "nested", "PCR", "failed", "for", "any", "of", "the", "fragments,", "using", "different", "primers.", "The", "detection", "limit", "was", "5%", "mutated", "DNA", "and", "duplicate", "experiments", "revealed", "good", "reproducibility", "(85%)[28].", "From", "72", "of", "the", "737", "patients", "with", "sufficient", "DNA", "yield,", "one", "or", "more", "fragments", "of", "the", "mutation", "cluster", "region", "could", "not", "be", "amplified", "and", "these", "patients", "were", "not", "included", "in", "this", "study." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The majority of somatic mutations in the APC gene are found within the mutation cluster region (codons 1286–1520). Mutation analysis of the mutation cluster region was performed on adenocarcinoma DNA using nested PCR for amplification of the mutation cluster region as four overlapping DNA fragments followed by direct sequencing of purified fragments, as previously described [28]. An alternative nested PCR strategy was performed when nested PCR failed for any of the fragments, using different primers. The detection limit was 5% mutated DNA and duplicate experiments revealed good reproducibility (85%)[28]. From 72 of the 737 patients with sufficient DNA yield, one or more fragments of the mutation cluster region could not be amplified and these patients were not included in this study.
2386495-04-Results-p02
[ "DNA", "sequencing", "of", "APC", "exon", "1", "in", "patient", "C157", "revealed", "the", "c.70C", ">", "T", "substitution", "which", "introduces", "a", "nonsense", "mutation", "in", "codon", "24", "APC", " ", "exon", "4", "in", "patient", "3765,", "c.423-1662_531+1825del3595,", "was", "detected", "by", "RNA-based", "PTT", "with", "subsequent", "cDNA", "sequencing", "and", "verified", "by", "long-range", "PCR", "on", "genomic", "DNA.", "We", "could", "not", "detect", "this", "deletion", "with", "MLPA", "even", "though", "a", "probe", "for", "exon", "4", "is", "included", "in", "the", "MLPA", "kit", "(see", "the", "discussion).", "Detection", "of", "the", "large", "deletion", "in", "patient", "C591,", "encompassing", "APC", " ", "exons", "13", "through", "the", "5'", "part", "of", "exon", "15,", "was", "carried", "out", "with", "MLPA.", "The", "deletion", "in", "patient", "2136", "was", "identified", "by", "PTT", "and", "subsequent", "DNA", "sequencing." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 21, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
DNA sequencing of APC exon 1 in patient C157 revealed the c.70C > T substitution which introduces a nonsense mutation in codon 24 APC exon 4 in patient 3765, c.423-1662_531+1825del3595, was detected by RNA-based PTT with subsequent cDNA sequencing and verified by long-range PCR on genomic DNA. We could not detect this deletion with MLPA even though a probe for exon 4 is included in the MLPA kit (see the discussion). Detection of the large deletion in patient C591, encompassing APC exons 13 through the 5' part of exon 15, was carried out with MLPA. The deletion in patient 2136 was identified by PTT and subsequent DNA sequencing.
2386495-03-Methods-p01
[ "**", "IGNORE", "LINE", "**" ]
[ 0, 0, 0, 0 ]
** IGNORE LINE **
1557864-02-Background-p01
[ "If", "it", "would", "be", "possible", "to", "predict", "primary", "platinum", "resistance,", "patients", " ", "might", "be", "spared", "an", "ineffective", "but", "toxic", "platinum-containing", "therapy", "and", "might", "benefit", "from", "an", "early", "therapy", "with", "different", "drugs.", "Recently,", "several", "molecular", "profiling", "studies,", "including", "our", "study,", "have", "revealed", "gene", "sets", "that", "can", "predict", "response", "to", "platinum-based", "chemotherapy", "in", "ovarian", "cancer", "[4-6].", "We", "discovered", "a", "nine-gene", "set", "which", "predicts", "response", "with", "a", "sensitivity", "of", "89%", "and", "a", "specificity", "of", "59%", "[5].", "One", "of", "these", "nine", "genes", "was", "proliferating", "cell", "nuclear", "antigen", "(PCNA).", "PCNA", "is", "a", "DNA", "sliding", "clamp", "that", "interacts", "with", "several", "proteins", "involved", "in", "cell", "cycle", "control,", "DNA", "methylation,", "DNA", "replication", "and", "DNA", "repair", "including", "mismatch", "repair", "[7].", "In", "this", "study,", "we", "have", "focused", "on", "DNA", "mismatch", "repair", "and", "its", "role", "in", "platinum-based", "chemotherapy", "resistance", "in", "ovarian", "cancer." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
If it would be possible to predict primary platinum resistance, patients might be spared an ineffective but toxic platinum-containing therapy and might benefit from an early therapy with different drugs. Recently, several molecular profiling studies, including our study, have revealed gene sets that can predict response to platinum-based chemotherapy in ovarian cancer [4-6]. We discovered a nine-gene set which predicts response with a sensitivity of 89% and a specificity of 59% [5]. One of these nine genes was proliferating cell nuclear antigen (PCNA). PCNA is a DNA sliding clamp that interacts with several proteins involved in cell cycle control, DNA methylation, DNA replication and DNA repair including mismatch repair [7]. In this study, we have focused on DNA mismatch repair and its role in platinum-based chemotherapy resistance in ovarian cancer.
2386495-01-Abstract-p01
[ "Sixty-one", "different", "APC", "mutations", "in", "81", "of", "the", "96", "families", "were", "identified", "and", "27", "of", "those", "are", "novel.", "We", "have", "previously", "shown", "that", "6", "of", "the", "96", "patients", "carried", "biallelic", "MUTYH", "mutations.", "The", "9", "mutation-negative", "cases", "all", "display", "an", "attenuated", "or", "atypical", "phenotype.", "Probands", "with", "a", "genotype", "(codon", "1250–1464)", "predicting", "a", "severe", "phenotype", "had", "a", "median", "age", "at", "diagnosis", "of", "21.8", "(range,", "11–49)", "years", "compared", "with", "34.4", "(range,", "14–57)", "years", "among", "those", "with", "mutations", "outside", "this", "region", "(P", "<", "0.017).", "Dense", "polyposis", "(>", "1000)", "occurred", "in", "75%", "of", "the", "probands", "with", "a", "severe", "phenotype", "compared", "with", "30%", "in", "those", "with", "mutations", "outside", "this", "region.", "The", "morbidity", "21.8", "(range,", "11–49)", "years", " ", "compared", "with", "34.4", "(range,", "14–57)", "years", "among", "those", "with", "mutations", "outside", "this", "region", "(P", "<", "0.017).", "Dense", "polyposis", "(>", "1000)", "occurred", "in", "75%", "of", "the", "probands", "with", "a", "severe", "phenotype", "compared", "with", "30%", "in", "those", "with", "mutations", "outside", "this", "region.", "The", "morbidity", "in", "colorectal", "cancer", "among", "probands", "was", "25%", "at", "a", "mean", "age", "of", "37.5", "years", "and", "29%", "at", "a", "mean", "age", "of", "46.6", "years." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 17, 15, 16, 16, 16, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Sixty-one different APC mutations in 81 of the 96 families were identified and 27 of those are novel. We have previously shown that 6 of the 96 patients carried biallelic MUTYH mutations. The 9 mutation-negative cases all display an attenuated or atypical phenotype. Probands with a genotype (codon 1250–1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11–49) years compared with 34.4 (range, 14–57) years among those with mutations outside this region (P < 0.017). Dense polyposis (> 1000) occurred in 75% of the probands with a severe phenotype compared with 30% in those with mutations outside this region. The morbidity 21.8 (range, 11–49) years compared with 34.4 (range, 14–57) years among those with mutations outside this region (P < 0.017). Dense polyposis (> 1000) occurred in 75% of the probands with a severe phenotype compared with 30% in those with mutations outside this region. The morbidity in colorectal cancer among probands was 25% at a mean age of 37.5 years and 29% at a mean age of 46.6 years.
3034663-03-Methods-p01
[ "DNA", "from", "blood", "cells", "(", "familial", "Controls", " ", "and", "sporadic", "and", "familial", "CRC", "cases" ]
[ 0, 0, 0, 0, 0, 17, 9, 0, 0, 0, 0, 0, 0, 0 ]
DNA from blood cells ( familial Controls and sporadic and familial CRC cases
3034663-02-Background-p01
[ "The", "results", "of", "sequence-based", "genetic", "tests", "may", "be", "reported", "to", "physicians", "as:", "1)", "positive,", "in", "which", "a", "mutation", "that", "clearly", "disrupts", "gene", "function", "is", "detected", "and", "is", "highly", "likely", "to", "have", "clinical", "consequences;", "2)", "a", "genetic", "variant", "is", "detected", "but", "it", "is", "not", "known", "whether", "the", "variant", "has", "any", "effect", "on", "gene", "function", "that", "might", "confer", "an", "increased", "cancer", "risk", "(these", "variants", "are", "known", "as", "variants", "of", "uncertain/unclassified", "significance", "or", "unclassified", "variants", "[UVs]);", "and", "3)", "negative,", "in", "which", "deleterious", "variant", "or", "UV", "is", "detected", "[1]." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The results of sequence-based genetic tests may be reported to physicians as: 1) positive, in which a mutation that clearly disrupts gene function is detected and is highly likely to have clinical consequences; 2) a genetic variant is detected but it is not known whether the variant has any effect on gene function that might confer an increased cancer risk (these variants are known as variants of uncertain/unclassified significance or unclassified variants [UVs]); and 3) negative, in which deleterious variant or UV is detected [1].
2386495-04-Results-p02
[ "Three", "patients", "(C107,", "C257,", "and", "C505),", "negative", "for", "mutations", "in", "APC,", "were", "reported", "as", "de", "novo", "cases", "with", "no", "known", "family", "history", "of", "FAP.", "These", "patients", "where", "all", "screened", "for", "APC", "mutations", "present", "as", "low-frequency", "alleles", "using", "SSCP/HD.", "We", "did", "not", "detect", "any", "signs", "of", "low-frequency", "mutations", "in", "patients", "C257", "and", "C505.", "However,", "in", "patient", "C107,", "aberrant", "bands,", "possibly", "originating", "from", "formation", "of", "heteroduplexes,", "was", "detected", "by", "SSCP/HD", "in", "a", "very", "low", "fraction", "of", "her", "blood", "lymphocytes.", "The", "c.2700_2701delTC", "mutation,", "which", "results", "in", "frame", "shift", "at", "codon", "900,", "was", "found", "by", "sequencing", "of", "the", "aberrant", "bands", "excised", "from", "the", "SSCP/HD", "gel", "(Figure", "2A).", "The", "mutation", "was", "detected", "in", "approximately", "one-third", "of", "the", "analyzed", "tumor-derived", "cells", "extracted", "from", "paraffin-embedded", "tissue", "by", "DNA", "sequencing", "(Figure", "2B).", "The", "mutation", "was", "not", "detectable", "at", "all", "in", "the", "sequence", "determination", "of", "DNA", "extracted", "from", "blood", "lymphocytes", "deletion", "of", "86", "bp", "in", "exon", "15", " ", "to", "a", "deletion", "of", "the", "whole", "APC", "gene", "(Figure", "1C).", "Three", "of", "these", "deletions", "have", "not,", "to", "the", "best", "of", "the", "authors'", "knowledge,", "been", "described", "earlier.", "The", "deletion", "encompassing", "APC", "exon", "4", " ", "in", "patient", "3765,", "c.423-1662_531+1825del3595,", "was", "detected", "by", "RNA-based", "PTT", "with", "subsequent", "cDNA", "sequencing", "and", "verified", "by", "long-range", "PCR", "on", "genomic", "DNA.", "We", "could", "not", "detect", "this", "deletion", "with", "MLPA", "even", "though", "a", "probe", "for", "exon", "4", "is", "included", "in", "the", "MLPA", "kit", "(see", "the", "discussion).", "Detection", "of", "the", "large", "deletion", "in", "patient", "C591,", "encompassing", "APC", "exons", "13", "through", "the", "5'", "part", "of", "exon", "15,", "was", "carried", "out", "with", "MLPA.", "The", "deletion", "in", "patient", "2136", "was", "identified", "by", "PTT", "and", "subsequent", "DNA", "sequencing." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 4, 5, 6, 6, 6, 6, 6, 6, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 6, 6, 6, 6, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Three patients (C107, C257, and C505), negative for mutations in APC, were reported as de novo cases with no known family history of FAP. These patients where all screened for APC mutations present as low-frequency alleles using SSCP/HD. We did not detect any signs of low-frequency mutations in patients C257 and C505. However, in patient C107, aberrant bands, possibly originating from formation of heteroduplexes, was detected by SSCP/HD in a very low fraction of her blood lymphocytes. The c.2700_2701delTC mutation, which results in frame shift at codon 900, was found by sequencing of the aberrant bands excised from the SSCP/HD gel (Figure 2A). The mutation was detected in approximately one-third of the analyzed tumor-derived cells extracted from paraffin-embedded tissue by DNA sequencing (Figure 2B). The mutation was not detectable at all in the sequence determination of DNA extracted from blood lymphocytes deletion of 86 bp in exon 15 to a deletion of the whole APC gene (Figure 1C). Three of these deletions have not, to the best of the authors' knowledge, been described earlier. The deletion encompassing APC exon 4 in patient 3765, c.423-1662_531+1825del3595, was detected by RNA-based PTT with subsequent cDNA sequencing and verified by long-range PCR on genomic DNA. We could not detect this deletion with MLPA even though a probe for exon 4 is included in the MLPA kit (see the discussion). Detection of the large deletion in patient C591, encompassing APC exons 13 through the 5' part of exon 15, was carried out with MLPA. The deletion in patient 2136 was identified by PTT and subsequent DNA sequencing.
1619718-05-Discussion-p04
[ "Loss", "of", "expression", "of", "the", "DNA", "repair", "gene", "MGMT", "is", "associated", "with", "methylation", "of", "the", "promoter", "region45,51,52", "and", "the", "latter", "change", "has", "been", "linked", "causatively", "with", "G:C", "to", "A:T", "transition", "mutations", "in", "TP53.53", "In", "the", "present", "study,", "complete", "or", "partial", "loss", "of", "expression", "of", "MGMT", "coincided", "with", "aberrant", "nuclear", "expression", "of", "p53", "in", "three", "serrated", "polyps", "with", "dysplasia", "(Figure", "2),", "but", "not", "in", "the", "single", "tubular", "adenoma", "with", "aberrant", "p53", "expression.", "Only", "one", "previous", "study", "has", "attempted", "to", "correlate", "MGMT", "and", "p53", "expression", "in", "colorectal", "polyps.45", "In", "that", "study,", "4.3%", "of", "adenomas", "showed", "aberrant", "p53", "expression", "but", "none", "had", "loss", "of", "MGMT.", "It", "is", "possible", "that", "the", "link", "between", "MGMT", "silencing", "and", "TP53", "mutation", "is", "more", "evident", "in", "the", "serrated", "pathway", "than", "in", "the", "adenoma–carcinoma", "sequence.", "The", "frequency", "of", "TP53", "mutation", "in", "SAs", "has", "ranged", "from", "5", "to", "50%", "in", "the", "literature.39,41,54", "Although", "a", "link", "between", "MGMT", "loss", "and", "aberrant", "expression", "of", "p53", "One", "MGMT", "inactivation", " ", "predisposes", "to", "G:T", "mismatches", "and", "chromosomal", "instability", "through", "futile", "cycles", "of", "excision", "and", "repair", "as", "well", "as", "to", "mutation", "of", "KRAS", "and", "TP53.9", "Partial", "methylation", "of", "MLH1", "may", "also", "lead", "to", "low-level", "microsatellite", "instability.37" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 8, 8, 8, 11, 7, 8, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Loss of expression of the DNA repair gene MGMT is associated with methylation of the promoter region45,51,52 and the latter change has been linked causatively with G:C to A:T transition mutations in TP53.53 In the present study, complete or partial loss of expression of MGMT coincided with aberrant nuclear expression of p53 in three serrated polyps with dysplasia (Figure 2), but not in the single tubular adenoma with aberrant p53 expression. Only one previous study has attempted to correlate MGMT and p53 expression in colorectal polyps.45 In that study, 4.3% of adenomas showed aberrant p53 expression but none had loss of MGMT. It is possible that the link between MGMT silencing and TP53 mutation is more evident in the serrated pathway than in the adenoma–carcinoma sequence. The frequency of TP53 mutation in SAs has ranged from 5 to 50% in the literature.39,41,54 Although a link between MGMT loss and aberrant expression of p53 One MGMT inactivation predisposes to G:T mismatches and chromosomal instability through futile cycles of excision and repair as well as to mutation of KRAS and TP53.9 Partial methylation of MLH1 may also lead to low-level microsatellite instability.37
1557864-03-Methods-p02
[ "**", "IGNORE", "LINE", "**" ]
[ 0, 0, 0, 0 ]
** IGNORE LINE **
3034663-03-Methods-p01
[ "Families", "carrying", "the", "p.Lys618Ala", " ", "variant" ]
[ 0, 0, 0, 5, 0, 0 ]
Families carrying the p.Lys618Ala variant
3034663-03-Methods-p01
[ "Genotyping", "of", "the", "MLH1", "p.Lys618Ala", "variant" ]
[ 0, 0, 0, 0, 0, 0 ]
Genotyping of the MLH1 p.Lys618Ala variant
3034663-04-Results-p01
[ "In", "one", "of", "the", "families", "with", "LS,", "the", "index", "subject", "was", "heterozygous", "for", "a", "pathogenic", "MLH1", "variant", "(c.767C>T;", "p.Arg226X)", "and", "the", "p.Lys618Ala", "variant.", "Two", "of", "his", "offspring,", "who", "were", "diagnosed", "with", "CRC", "at", "the", "ages", "of", "36", "and", "39", "years,", "carried", "the", "deleterious", "variant", "but", "not", "the", "p.Lys618Ala", "variant.", "An", "unaffected", "daughter", "(III-12)", "carried", "the", "p.Lys618Ala", "variant", "but", "not", "the", "deleterious", "variant.", "Two", "nephews", "(III-3;", "III-4)", "were", "also", "diagnosed", "with", "CRC", "at", "the", "ages", "of", "30", "and", "42", "years", "and", "they", "carried", "only", "the", "deleterious", "variant.", "Two", "other", "healthy", "nephews", "(III-6;", "III-7)", "had", "the", "wild", "types", "of", "the", "two", "variants", "(Family", "#1,", "Figure", "2)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
In one of the families with LS, the index subject was heterozygous for a pathogenic MLH1 variant (c.767C>T; p.Arg226X) and the p.Lys618Ala variant. Two of his offspring, who were diagnosed with CRC at the ages of 36 and 39 years, carried the deleterious variant but not the p.Lys618Ala variant. An unaffected daughter (III-12) carried the p.Lys618Ala variant but not the deleterious variant. Two nephews (III-3; III-4) were also diagnosed with CRC at the ages of 30 and 42 years and they carried only the deleterious variant. Two other healthy nephews (III-6; III-7) had the wild types of the two variants (Family #1, Figure 2).
1334229-03-Methods-p02
[ "Amplification", "of", "exon", "3", "of", "the", "CTNNB1", "gene", "entailed", "a", "semi-nested", "PCR", "strategy,", "which", "covered", "codons", "33,", "37,", "41", "and", "45.", "Flank", "PCR", "was", "performed", "to", "generate", "a", "308", "bp", "fragment", "(primers,", "forward:", "5'-CCAATCTACTAATGCTAATACTG-3',", "reverse:", "5'-GCATTCTGACTTTCAGTAAGGC-3')", "that", "was", "used", "in", "a", "1:100", "dilution", "for", "amplification", "of", "the", "final", "PCR", "product", "(primers,", "forward:", "5'-CCAATCTACTAATGCTAATACTG-3',", "reverse:", "5'-CTTCCTCAGGATTGCCTTTACC-3').", "In", "each", "PCR,", "one", "round", "of", "35", "cycles", "was", "performed." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Amplification of exon 3 of the CTNNB1 gene entailed a semi-nested PCR strategy, which covered codons 33, 37, 41 and 45. Flank PCR was performed to generate a 308 bp fragment (primers, forward: 5'-CCAATCTACTAATGCTAATACTG-3', reverse: 5'-GCATTCTGACTTTCAGTAAGGC-3') that was used in a 1:100 dilution for amplification of the final PCR product (primers, forward: 5'-CCAATCTACTAATGCTAATACTG-3', reverse: 5'-CTTCCTCAGGATTGCCTTTACC-3'). In each PCR, one round of 35 cycles was performed.
3034663-04-Results-p01
[ "Twenty-seven", "individuals", "were", "heterozygous", "for", "the", "p.Lys618Ala", "variant", "(Figure", "1);", "11", "were", "controls", "(11/411,", "2.68%),", "nine", "were", "CRC", "patients", "from", "the", "sporadic", "group", "(9/373,", "2.41%)", "and", "seven", "were", "CRC", "patients", "from", "the", "familial", "group", "(7/250,", "2.8%).", "None", "of", "the", "individuals", "was", "homozygous", "for", "the", "minor", "allele." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Twenty-seven individuals were heterozygous for the p.Lys618Ala variant (Figure 1); 11 were controls (11/411, 2.68%), nine were CRC patients from the sporadic group (9/373, 2.41%) and seven were CRC patients from the familial group (7/250, 2.8%). None of the individuals was homozygous for the minor allele.
3034663-03-Methods-p02
[ "Microsatellite", "instability", "and", "MLH1", "immunohistochemical", "expression" ]
[ 0, 0, 0, 0, 0, 0 ]
Microsatellite instability and MLH1 immunohistochemical expression
1334229-01-Abstract-p01
[ "Background" ]
[ 0 ]
Background
2275286-03-Methods-p01
[ "Microsatellite", "instability", "analysis" ]
[ 0, 0, 0 ]
Microsatellite instability analysis
3034663-05-Discussion-p02
[ "Herein,", "we", "describe", "the", "coexistence", "of", "the", "p.Lys618Ala", "variant", "with", "deleterious", "variants", "in", "another", "two", "unrelated", "LS", "families.", "In", "one", "family,", "the", "allele", "distribution", "of", "the", "pathogenic", "and", "unclassified", "variant", "was", "in", "trans,", "in", "the", "other", "family", "the", "pathogenic", "variant", "was", "detected", "in", "the", "MSH6", "gene", "and", "only", "the", "deleterious", "variant", "co-segregated", "with", "the", "disease", "in", "both", "families.", "This", "evidence", "indicates", "that", "the", "p.Lys618Ala", "variant", "is", "not", "deleterious." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Herein, we describe the coexistence of the p.Lys618Ala variant with deleterious variants in another two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. This evidence indicates that the p.Lys618Ala variant is not deleterious.
1619718-04-Results-p03
[ "Sixty-two", "TAs,", "22", "TVAs/VAs,", "15", "SAs", "and", "10", "MPs", "were", "immunostained", "for", "p53.", "Weak", "expression", "of", "nuclear", "p53", "occurred", "frequently", "within", "the", "proliferative", "compartment", "in", "all", "types", "of", "polyps", "and", "was", "ignored.", "Aberrant", "p53", "expression", "was", "observed", "in", "only", "four", "polyps:", "one", "TA,", "one", "p53", ".", "Weak", "expression", "of", "nuclear", "p53", "occurred", "frequently", "within", "the", "proliferative", "compartment", "in", "all", "types", "of", "polyps", "and", "was", "ignored.", "Aberrant", "p53", "expression", "was", "observed", "in", "only", "four", "polyps:", "one", "15", "adenomas", "adenomas", " ", "with", "no", "MGMT", "loss", "but", "in", "4/8", "(50%)", "adenomas", "with", "MGMT", "loss", "(P", "<", "0.04).", "Since", "there", "were", "few", "KRAS", "mutations", "in", "this", "subset", "and", "most", "KRAS", "mutations", "(5/7)", "were", "G→A,", "it", "was", "not", "possible", "to", "demonstrate", "an", "association", "between", "MGMT", "loss", "and", "G→A", "mutation", "in", "KRAS." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 21, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Sixty-two TAs, 22 TVAs/VAs, 15 SAs and 10 MPs were immunostained for p53. Weak expression of nuclear p53 occurred frequently within the proliferative compartment in all types of polyps and was ignored. Aberrant p53 expression was observed in only four polyps: one TA, one p53 . Weak expression of nuclear p53 occurred frequently within the proliferative compartment in all types of polyps and was ignored. Aberrant p53 expression was observed in only four polyps: one 15 adenomas adenomas with no MGMT loss but in 4/8 (50%) adenomas with MGMT loss (P < 0.04). Since there were few KRAS mutations in this subset and most KRAS mutations (5/7) were G→A, it was not possible to demonstrate an association between MGMT loss and G→A mutation in KRAS.
2275286-01-Abstract-p01
[ "Thirty-four", "out", "of", "the", "146", "colorectal", "cancers", "(CRCs,", "23.2%", ")", "were", "MSI,", "including", "19", "MSI-H", "CRCs", "and", "15", "MSI-L", "CRCS.", "Negative", "staining", "for", "MSH2", "was", "found", "in", "8", "CRCs,", "negative", "staining", "for", "MSH6", "was", "found", "in", "6", "CRCs.", "One", "MSI-H", "CRC", "was", "negative", "for", "both", "MSH6", "and", "MSH2.", "Seventeen", "CRCs", "stained", "negatively", "for", "MLH1.", "MLH1", "promoter", "methylation", "was", "determined", "in", "34", "MSI", "CRCs.", "Hypermethylation", "of", "the", "MLH1", "promoter", "occurred", "in", "14", "(73.7%)", "out", "of", "19", "MSI-H", "CRCs", "and", "5", "(33.3%)", "out", "of", "15", "MSI-L", "CRCs.", "Among", "the", "34", "MSI", "carriers", "and", "one", "MSS", "CRC", "with", "MLH1", "negative", "staining,", "8", "had", "a", "MMR", "gene", "germline", "mutation,", "which", "accounted", "for", "23.5%", "of", "all", "MSI", "colorectal", "cancers", "and", "5.5%", "of", "all", "the", "colorectal", "cancers.", "Five", "patients", "harbored", "MSH2", "germline", "mutations,", "and", "three", "146", " ", "prospectively", "recruited", "consecutive", "patients", "with", "clinically", "proven", "colorectal", "cancer,", "MSI", "carriers", "were", "identified", "by", "analysis", "of", "tumor", "tissue", "using", "multiplex", "fluorescence", "polymerase", "chain", "reaction", "(PCR)", "using", "the", "NCI", "recommended", "panel", "and", "classified", "into", "microsatellite", "instability-low", "(MSI-L),", "microsatellite", "instability-high", "(MSI-H)", "and", "microsatellite", "stable", "(MSS)", "groups.", "Immunohistochemical", "staining", "for", "MSH2,", "MSH6", "and", "MLH1", "on", "tissue", "microarrays", "(TMAs)", "was", "performed,", "and", "methylation", "of", "the", "MLH1", "promoter", "was", "analyzed", "by", "quantitative", "methylation", "specific", "PCR", "(MSP).", "Germline", "mutation", "analysis", "of", "blood", "samples", "was", "performed", "for", "MSH2,", "MSH6", "and", "MLH1", "genes." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Thirty-four out of the 146 colorectal cancers (CRCs, 23.2% ) were MSI, including 19 MSI-H CRCs and 15 MSI-L CRCS. Negative staining for MSH2 was found in 8 CRCs, negative staining for MSH6 was found in 6 CRCs. One MSI-H CRC was negative for both MSH6 and MSH2. Seventeen CRCs stained negatively for MLH1. MLH1 promoter methylation was determined in 34 MSI CRCs. Hypermethylation of the MLH1 promoter occurred in 14 (73.7%) out of 19 MSI-H CRCs and 5 (33.3%) out of 15 MSI-L CRCs. Among the 34 MSI carriers and one MSS CRC with MLH1 negative staining, 8 had a MMR gene germline mutation, which accounted for 23.5% of all MSI colorectal cancers and 5.5% of all the colorectal cancers. Five patients harbored MSH2 germline mutations, and three 146 prospectively recruited consecutive patients with clinically proven colorectal cancer, MSI carriers were identified by analysis of tumor tissue using multiplex fluorescence polymerase chain reaction (PCR) using the NCI recommended panel and classified into microsatellite instability-low (MSI-L), microsatellite instability-high (MSI-H) and microsatellite stable (MSS) groups. Immunohistochemical staining for MSH2, MSH6 and MLH1 on tissue microarrays (TMAs) was performed, and methylation of the MLH1 promoter was analyzed by quantitative methylation specific PCR (MSP). Germline mutation analysis of blood samples was performed for MSH2, MSH6 and MLH1 genes.
3034663-03-Methods-p02
[ "MLH1", "promoter", "hypermethylation", "by", "Methylation", "Sensitive", "Multiplex", "Ligation-dependent", "Probe", "Amplification", "(MS-MLPA),", "and", "BRAF", "p.Val600Glu", "mutation", "by", "direct", "sequencing", "from", "tumor", "DNA", "was", "also", "assess", "when", "MLH1", "loss", "of", "expression", "relative", "p.Lys618Ala", " ", "carrier", "cases", "in", "the", "familial", "group", "(seven", "index", "subjects", "and", "one", "relative)", "were", "also", "analysed", "for", "MLH1", "protein", "expression", "using", "immunohistochemistry", "and", "anti-MLH1", "antibodies", "(PharMingen,", "CA,", "USA)", "as", "described", "elsewhere", "[7].", "Tumour", "cells", "were", "judged", "negative", "for", "protein", "expression", "only", "if", "they", "lacked", "staining", "in", "a", "sample", "in", "which", "normal", "colonocytes", "and", "stroma", "cells", "were", "stained.", "If", "no", "immunostaining", "of", "normal", "tissue", "could", "be", "demonstrated,", "the", "results", "were", "considered", "unreliable." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 7, 8, 8, 8, 9, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
MLH1 promoter hypermethylation by Methylation Sensitive Multiplex Ligation-dependent Probe Amplification (MS-MLPA), and BRAF p.Val600Glu mutation by direct sequencing from tumor DNA was also assess when MLH1 loss of expression relative p.Lys618Ala carrier cases in the familial group (seven index subjects and one relative) were also analysed for MLH1 protein expression using immunohistochemistry and anti-MLH1 antibodies (PharMingen, CA, USA) as described elsewhere [7]. Tumour cells were judged negative for protein expression only if they lacked staining in a sample in which normal colonocytes and stroma cells were stained. If no immunostaining of normal tissue could be demonstrated, the results were considered unreliable.
1619718-05-Discussion-p03
[ "Colorectal", "polyps", "have", "traditionally", "been", "classified", "into", "distinct", "histogenetic", "types", "that", "may", "progress", "to", "CRC", "through", "independent", "pathways", "of", "colorectal", "tumorigenesis", "(Table", "2).", "However,", "in", "addition", "to", "the", "two", "‘classical’", "pathways", "to", "CRC", "shown", "in", "Table", "2,", "there", "may", "be", "‘fusion’", "pathways", "that", "combine", "mechanisms", "associated", "with", "both", "adenomas", " ", "and", "serrated", "polyps.", "This", "would", "explain", "why", "many", "CRCs", "display", "phenotypes", "associated", "with", "serrated", "polyps", "as", "well", "as", "adenomas", ".44", "Three", "possible", "examples", "of", "such", "fusion", "pathways", "are", "shown", "in", "Table", "3.", "It", "is", "difficult", "to", "observe", "directly", "the", "actual", "point", "of", "transition", "from", "benign", "to", "malignant", "colorectal", "lesions.", "Once", "the", "key", "rate-limiting", "step", "is", "achieved", "it", "is", "likely", "that", "the", "transition", "to", "cancer", "occurs", "rapidly", "and", "the", "precursor", "lesion", "is", "then", "overtaken", "by", "the", "malignancy.", "Changes", "leading", "to", "inactivation", "of", "either", "TP535", "or", "the", "DNA", "mismatch", "repair", "gene", "MLH113", "are", "likely", "to", "be", "two", "such", "rate-limiting", "mechanisms.", "Only", "a", "single", "instance", "of", "loss", "of", "expression", "of", "MLH1", "was", "observed", "in", "the", "present", "series", "of", "polyps", "and", "the", "adenoma", " ", "in", "question", "was", "inferred", "to", "be", "from", "a", "patient", "with", "Lynch", "syndrome.24" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Colorectal polyps have traditionally been classified into distinct histogenetic types that may progress to CRC through independent pathways of colorectal tumorigenesis (Table 2). However, in addition to the two ‘classical’ pathways to CRC shown in Table 2, there may be ‘fusion’ pathways that combine mechanisms associated with both adenomas and serrated polyps. This would explain why many CRCs display phenotypes associated with serrated polyps as well as adenomas .44 Three possible examples of such fusion pathways are shown in Table 3. It is difficult to observe directly the actual point of transition from benign to malignant colorectal lesions. Once the key rate-limiting step is achieved it is likely that the transition to cancer occurs rapidly and the precursor lesion is then overtaken by the malignancy. Changes leading to inactivation of either TP535 or the DNA mismatch repair gene MLH113 are likely to be two such rate-limiting mechanisms. Only a single instance of loss of expression of MLH1 was observed in the present series of polyps and the adenoma in question was inferred to be from a patient with Lynch syndrome.24
3034663-04-Results-p01
[ "Allelic", "and", "genotypic", "frequencies", "and", "Hardy-Weinberg", "equilibrium" ]
[ 0, 0, 0, 0, 0, 0, 0 ]
Allelic and genotypic frequencies and Hardy-Weinberg equilibrium
1360090-02-Background-p01
[ "**", "IGNORE", "LINE", "**" ]
[ 0, 0, 0, 0 ]
** IGNORE LINE **
1334229-04-Results-p02
[ "Next,", "we", "compared", "the", "patient", "and", "tumour", "characteristics", "of", "tumours", "harbouring", "a", "truncating", "APC", "and/or", "an", "activating", "K-ras", "mutation", "to", "those", "of", "tumours", "without", "hMLH1", "expression,", "and", "these", "results", "are", "presented", "in", "table", "4.", "Patients", "harbouring", "hMLH1", "deficient", "tumours", "were", "slightly", "older", "when", "diagnosed", "with", "colorectal", "cancer", "(69.3", "yr", "(68.0–70.5)", "versus", "67.8", "(67.4–68.3),", "P", "=", "0.03),", "were", "relatively", "less", "frequently", "men", "(40%", "versus", "58%,", "P", "=", "0.02).", "Tumours", "without", "hMLH1", "expression", "occurred", "relatively", "more", "frequently", "in", "the", "proximal", "colon", "(P", "<", "0.001)", "and", "relatively", "more", "frequently", "showed", "poor", "differentiation", "or", "are", "undifferentiated", "(P", "<", "0.001)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Next, we compared the patient and tumour characteristics of tumours harbouring a truncating APC and/or an activating K-ras mutation to those of tumours without hMLH1 expression, and these results are presented in table 4. Patients harbouring hMLH1 deficient tumours were slightly older when diagnosed with colorectal cancer (69.3 yr (68.0–70.5) versus 67.8 (67.4–68.3), P = 0.03), were relatively less frequently men (40% versus 58%, P = 0.02). Tumours without hMLH1 expression occurred relatively more frequently in the proximal colon (P < 0.001) and relatively more frequently showed poor differentiation or are undifferentiated (P < 0.001).
1619718-01-Abstract-p01
[ "Aim" ]
[ 0 ]
Aim
1619718-05-Discussion-p02
[ "dysplastic", "serrated", "polyps:", "MP", "and", "SA" ]
[ 0, 0, 0, 0, 0, 0 ]
dysplastic serrated polyps: MP and SA
2386495-01-Abstract-p01
[ "Sixty-one", "different", "APC", "mutations", "in", "81", "of", "the", "96", "families", "were", "identified", "and", "27", "of", "those", "are", "novel.", "We", "have", "previously", "shown", "that", "6", "of", "the", "96", "patients", "carried", "biallelic", "MUTYH", "mutations.", "The", "9", "mutation-negative", "cases", "all", "display", "an", "attenuated", "or", "atypical", "phenotype.", "Probands", "with", "a", "genotype", "(codon", "1250–1464)", "families", ".", "Correlating", "the", "genotypes", "to", "the", "phenotypes", "could", "help", "to", "improve", "the", "diagnosis", "and", "follow-up", "of", "patients." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 10, 10, 10, 10, 10, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Sixty-one different APC mutations in 81 of the 96 families were identified and 27 of those are novel. We have previously shown that 6 of the 96 patients carried biallelic MUTYH mutations. The 9 mutation-negative cases all display an attenuated or atypical phenotype. Probands with a genotype (codon 1250–1464) families . Correlating the genotypes to the phenotypes could help to improve the diagnosis and follow-up of patients.
1373649-03-Methods-p01
[ "DNA", "preparation", "for", "genetic", "testing" ]
[ 0, 0, 0, 0, 0 ]
DNA preparation for genetic testing
1619718-01-Abstract-p01
[ "To", "establish", "and", "explain", "the", "pattern", "of", "molecular", "signatures", "across", "colorectal", "polyps." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
To establish and explain the pattern of molecular signatures across colorectal polyps.
1601966-03-Results-p05
[ "Up-regulation", "of", "mRNA", "expression", "in", "human", "chromosomal", "region", "20q11.22-q11.23", "(patient", "counts", "with", "coordinate", "up-regulation).", "Grayscale", "plot", "of", "cross-comparison", "of", "up-regulation", "patterns", "across", "patients", "for", "gene", "pairs", "in", "a", "particular", "region.", "Both,", "horizontal", "and", "vertical", "axes", "comprise", "the", "same", "genes", "in", "chromosomal", "order.", "In", "each", "square", "total", "counts", "of", "patients", "with", "consistent", "up-regulation", "in", "two", "genes", "are", "coded", "by", "different", "shades", "of", "gray.", "Dark", "squared", "regions", "along", "the", "diagonal", "indicate", "coordinated", "regulation", "in", "patient", "subgroups.", "Note,", "that", "many", "more", "patients", "show", "up-regulation", "as", "indicated", "by", "dark", "spots", "in", "this", "plot", "than", "down-regulation", "as", "indicated", "by", "dark", "spots", "in", "Figure", "14.", "The", "known", "most", "frequently", "up-regulated", "genes", "in", "this", "region", "are", "EIF2S2,", "AHCY,", "ITCH,", "DNCL2A,", "ITG4BP,", "C20orf24,", "NDRGL3,", "RPN2", "tumor", ";", "red:", "up", "in", "tumor).", "View", "in", "conjunction", "with", "Figures", "13", "and", "14." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Up-regulation of mRNA expression in human chromosomal region 20q11.22-q11.23 (patient counts with coordinate up-regulation). Grayscale plot of cross-comparison of up-regulation patterns across patients for gene pairs in a particular region. Both, horizontal and vertical axes comprise the same genes in chromosomal order. In each square total counts of patients with consistent up-regulation in two genes are coded by different shades of gray. Dark squared regions along the diagonal indicate coordinated regulation in patient subgroups. Note, that many more patients show up-regulation as indicated by dark spots in this plot than down-regulation as indicated by dark spots in Figure 14. The known most frequently up-regulated genes in this region are EIF2S2, AHCY, ITCH, DNCL2A, ITG4BP, C20orf24, NDRGL3, RPN2 tumor ; red: up in tumor). View in conjunction with Figures 13 and 14.
1266026-04-Results-p01
[ "Ages", "at", "cancer", "can", "be", "used", "to", "estimate", "likely", "numbers", "of", "oncogenic", "mutations", "required", "before", "transformation", "[3-6,11].", "Average", "ages", "for", "sporadic", "MSI+,", "MSI-,", "and", "HNPCC", "cancers", "were", "respectively", "71.5,", "67.5,", "and", "50.3", "years", "(Figure", "1A).", "For", "HNPCC", "cancers,", "estimated", "numbers", "of", "oncogenic", "mutations", "were", "between", "four", "and", "seven", "(95%", "credibility", "interval),", "with", "the", "most", "likely", "value", "of", "five", "mutations", "895", " ", "(87.6%)", "MSI-", "cancers", "and", "127", "(12.4%)", "MSI+", "cancers.", "The", "MSI+", "cancers", "were", "further", "classified", "as", "sporadic", "(N", "=", "98", "or", "9.6%", "of", "all", "cancers)", "or", "HNPCC", "(N", "=", "29", "or", "2.9%", "of", "all", "cancers)", "based", "on", "germline", "MLH1", "or", "MSH2", "mutations", "(Table", "1)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Ages at cancer can be used to estimate likely numbers of oncogenic mutations required before transformation [3-6,11]. Average ages for sporadic MSI+, MSI-, and HNPCC cancers were respectively 71.5, 67.5, and 50.3 years (Figure 1A). For HNPCC cancers, estimated numbers of oncogenic mutations were between four and seven (95% credibility interval), with the most likely value of five mutations 895 (87.6%) MSI- cancers and 127 (12.4%) MSI+ cancers. The MSI+ cancers were further classified as sporadic (N = 98 or 9.6% of all cancers) or HNPCC (N = 29 or 2.9% of all cancers) based on germline MLH1 or MSH2 mutations (Table 1).
2275286-03-Methods-p03
[ "**", "IGNORE", "LINE", "**" ]
[ 0, 0, 0, 0 ]
** IGNORE LINE **
1619718-04-Results-p01
[ "KRAS", "mutation", "occurred", "in", "26.5%", "and", "BRAF", "SSA", ").", "The", "three", "conventional", "adenomas", "with", "mutations", "of", "both", "BRAF", "and", "KRAS", "were", "among", "only", "four", "adenomas", "that", "had", "any", "BRAF", "mutations", "at", "all.", "Mutation", "frequencies", "for", "both", "KRAS", "and", "BRAF", "were", "distributed", "differently", "across", "the", "seven", "polyp", "groups", "(Table", "1)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
KRAS mutation occurred in 26.5% and BRAF SSA ). The three conventional adenomas with mutations of both BRAF and KRAS were among only four adenomas that had any BRAF mutations at all. Mutation frequencies for both KRAS and BRAF were distributed differently across the seven polyp groups (Table 1).
1601966-03-Results-p11
[ "14q24.3" ]
[ 0 ]
14q24.3
2386495-04-Results-p03
[ "Characterization", "of", "the", "mutation", "in", "patient", "C496.", "(A)", "Genomic", "sequence", "of", "the", "patient", "showing", "the", "c.835-7T", ">", "G", "mutation.", "The", "new", "splice", "site", "generated", "by", "the", "T", ">", "G", "substitution", "is", "indicated", "with", "a", "dashed", "line,", "the", "wildtype", "acceptor-splice", "site", "is", "underlined,", "and", "the", "regular", "start", "of", "exon", "8", "is", "indicated", "with", "an", "arrow.", "(B)", "cDNA", "sequence", "covering", "the", "exon", "7–8", "boundary,", "indicated", "with", "a", "dashed", "line.", "Shown", "below", "the", "sequence", "diagram", "is", "the", "interpretation", "of", "the", "sequence", "reflecting", "the", "two", "mRNA", "species", "present", "in", "the", "sample.", "The", "insertion", "of", "6", "bp", "owing", "to", "the", "introduction", "of", "a", "new", "splice", "site", "in", "the", "mutant", "allele", "is", "shown", "as", "a", "shaded", "area.", "Predicted", "amino-acid", "sequence", "of", "translation", "products", "are", "shown", "above", "and", "below", "the", "respective", "cDNA", "sequence." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Characterization of the mutation in patient C496. (A) Genomic sequence of the patient showing the c.835-7T > G mutation. The new splice site generated by the T > G substitution is indicated with a dashed line, the wildtype acceptor-splice site is underlined, and the regular start of exon 8 is indicated with an arrow. (B) cDNA sequence covering the exon 7–8 boundary, indicated with a dashed line. Shown below the sequence diagram is the interpretation of the sequence reflecting the two mRNA species present in the sample. The insertion of 6 bp owing to the introduction of a new splice site in the mutant allele is shown as a shaded area. Predicted amino-acid sequence of translation products are shown above and below the respective cDNA sequence.
1619718-04-Results-p01
[ "Mutation", "frequencies", "for", "both", "KRAS", "(P", "<", "0.0001)", "and", "BRAF", "(P", "<", "0.0001)", "are", "distributed", "differently", "across", "the", "seven", "classes", "of", "polyp", "(see", "Results", "for", "individual", "comparisons).", "Distribution", "of", "MGMT", "loss", "differs", "across", "the", "seven", "classes", "of", "polyp", "(P", "<", "0.001)." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Mutation frequencies for both KRAS (P < 0.0001) and BRAF (P < 0.0001) are distributed differently across the seven classes of polyp (see Results for individual comparisons). Distribution of MGMT loss differs across the seven classes of polyp (P < 0.001).
1334229-01-Abstract-p01
[ "CTNNB1", "mutations", "seem", "to", "be", "of", "minor", "importance", "in", "sporadic", "colorectal", "cancer.", "The", "main", "differences", "in", "tumour", "cancer", "APC", ",", "K-ras,", "CTNNB1", "genes,", "and", "expression", "of", "hMLH1", "were", "investigated.", "Additionally,", "tumours", "were", "divided", "in", "groups", "based", "on", "molecular", "features", "and", "compared", "with", "respect", "to", "patient's", "age", "at", "diagnosis,", "sex,", "family", "history", "of", "colorectal", "cancer,", "tumour", "sub-localisation,", "Dukes'", "stage", "and", "differentiation." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 21, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
CTNNB1 mutations seem to be of minor importance in sporadic colorectal cancer. The main differences in tumour cancer APC , K-ras, CTNNB1 genes, and expression of hMLH1 were investigated. Additionally, tumours were divided in groups based on molecular features and compared with respect to patient's age at diagnosis, sex, family history of colorectal cancer, tumour sub-localisation, Dukes' stage and differentiation.
1601966-03-Results-p11
[ "**", "IGNORE", "LINE", "**" ]
[ 0, 0, 0, 0 ]
** IGNORE LINE **
1373649-04-Results-and-discussion-p01
[ "**", "IGNORE", "LINE", "**" ]
[ 0, 0, 0, 0 ]
** IGNORE LINE **
2275286-04-Results-p02
[ "Clinical", "features", "of", "patients", "in", "MSI", "group", "with", "MMR", "gene", "mutations" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Clinical features of patients in MSI group with MMR gene mutations
1334229-01-Abstract-p01
[ "Results" ]
[ 0 ]
Results
3034663-03-Methods-p01
[ "No", "familial", "history", "of", "cancer", "was", "available", "from", "the", "control", "group.", "Patients", "diagnosed", "at", "an", "age", "over", "50", "years", "and", "not", "referred", "to", "Genetic", "Counselling", "Units", "were", "considered", "as", "sporadic", "CRC", "patients", "patients", ",", "250", "index", "subjects", "from", "families", "suspected", "of", "having", "LS", "[revised", "Bethesda", "Guidelines]", "and", "411", "controls).", "The", "controls", "were", "selected", "from", "the", "same", "hospitals,", "had", "no", "personal", "histories", "of", "cancer", "and", "had", "diagnoses", "unrelated", "to", "the", "variables", "of", "interest.", "They", "were", "matched", "for", "age,", "gender", "and", "race/ethnicity", "with", "the", "sporadic", "CRC", "patients." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
No familial history of cancer was available from the control group. Patients diagnosed at an age over 50 years and not referred to Genetic Counselling Units were considered as sporadic CRC patients patients , 250 index subjects from families suspected of having LS [revised Bethesda Guidelines] and 411 controls). The controls were selected from the same hospitals, had no personal histories of cancer and had diagnoses unrelated to the variables of interest. They were matched for age, gender and race/ethnicity with the sporadic CRC patients.
2275286-04-Results-p02
[ "The", "MSI", "state,", "mutation", "sites,", "and", "consequential", "changes", "in", "amino-acid", "sequences", "of", "MMR", "genes", "are", "summarized", "in", "Table", "4.", "In", "34", "MSI", "CRCs", "and", "one", "MSS", "CRC", "with", "MLH1", "negative", "staining,", "8", "had", "MMR", "gene", "germline", "mutations,", "accounting", "for", "22.9%", "of", "MSI", "colorectal", "cancers", "and", "5.5%", "of", "all", "colorectal", "cancers.", "Three", "patients", "had", "MSH6", "germline", "mutations", "and", "5", "had", "MSH2", "germline", "mutations;", "the", "clinical", "features", "of", "these", "patients", "are", "summarized", "in", "Table", "5.", "None", "of", "the", "patients", "had", "MLH1", "gene", "mutations.", "Seven", "patients", "in", "the", "MSI", "group", "had", "A/T", "heterozygosis", "in", "MSH6", "codon", "380", "of", "exon", "5,", "but", "it", "did", "not", "cause", "changes", "in", "the", "amino", "acid", "sequence.", "The", "germline", "mutations", "of", "the", "MSI-L", "and", "MSI-H", "CRCs", "are", "summarized", "in", "Table", "6.", "Six", "CRCs", "with", "mutations", "were", "MSI-H", "and", "two", "patients", "with", "mutations", "were", "MSI-L." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The MSI state, mutation sites, and consequential changes in amino-acid sequences of MMR genes are summarized in Table 4. In 34 MSI CRCs and one MSS CRC with MLH1 negative staining, 8 had MMR gene germline mutations, accounting for 22.9% of MSI colorectal cancers and 5.5% of all colorectal cancers. Three patients had MSH6 germline mutations and 5 had MSH2 germline mutations; the clinical features of these patients are summarized in Table 5. None of the patients had MLH1 gene mutations. Seven patients in the MSI group had A/T heterozygosis in MSH6 codon 380 of exon 5, but it did not cause changes in the amino acid sequence. The germline mutations of the MSI-L and MSI-H CRCs are summarized in Table 6. Six CRCs with mutations were MSI-H and two patients with mutations were MSI-L.
1266026-03-Methods-p01
[ "Quantitative", "analysis" ]
[ 0, 0 ]
Quantitative analysis
1334229-05-Discussion-p02
[ "The", "K-ras", "mutation", " ", "frequency", "of", "37%", "is", "in", "accordance", "with", "reported", "frequencies", "of", "30", "to", "60%", "[33-43].", "The", "frequency", "of", "37%", " ", "of", "truncating", "mutations", "in", "the", "mutation", "cluster", "region", "of", "APC", "in", "this", "study,", "however,", "seems", "low", "in", "comparison", "to", "the", "general", "assumption", "that", "most", "colorectal", "tumours", "harbour", "a", "mutation", "in", "the", "APC", "gene.", "When", "only", "reports", "from", "studies", "on", "sporadic", "rather", "than", "familial", "colorectal", "cancer", "or", "colorectal", "cancer", "cell", "lines", "are", "considered,", "the", "mutation", "frequencies", "are", "lower", "and", "vary", "between", "30", "and", "70%", "[17,44-49],", "and", "a", "population-based", "case-control", "study", "in", "the", "Netherlands", "reported", "a", "32%", "mutation", "frequency", "[50]." ]
[ 0, 0, 5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
The K-ras mutation frequency of 37% is in accordance with reported frequencies of 30 to 60% [33-43]. The frequency of 37% of truncating mutations in the mutation cluster region of APC in this study, however, seems low in comparison to the general assumption that most colorectal tumours harbour a mutation in the APC gene. When only reports from studies on sporadic rather than familial colorectal cancer or colorectal cancer cell lines are considered, the mutation frequencies are lower and vary between 30 and 70% [17,44-49], and a population-based case-control study in the Netherlands reported a 32% mutation frequency [50].
1557864-01-Abstract-p01
[ "Conclusion" ]
[ 0 ]
Conclusion
1619718-01-Abstract-p01
[ "Advanced", "colorectal", "polyps", "with", "the", "molecular", "and", "morphological", "features", "of", "serrated", "polyps", "and", "adenomas:", "concept", "of", "a", "‘fusion’", "pathway", "to", "colorectal", "cancer" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancer
1334229-05-Discussion-p01
[ "Mutations", "in", "exon", "3", "of", "the", "CTNNB1", "gene", "leading", "to", "loss", "of", "one", "of", "the", "phosphorylation", "sites", "were", "rare.", "Strikingly,", "all", "five", "of", "these", "mutations", "occurred", "in", "the", "proximal", "colon", "and", "three", "of", "these", "also", "had", "absent", "hMLH1", "expression.", "This", "may", "indicate", "that", "these", "proximal", "colon", "tumours,", "which", "often", "also", "show", "mismatch", "repair", "deficiency,", "are", "more", "likely", "to", "harbour", "CTNNB1", "mutations.", "This", "was", "also", "found", "in", "a", "study", "of", "microsatellite", "instable", "colorectal", "tumours", "[26].", "The", "WAVE", "screening", "technique", "has", "not", "been", "used", "previously", "for", "formalin-fixed,", "paraffin-embedded", "tissue,", "and", "therefore", "it", "seems", "plausible", "that", "samples", "harbouring", "a", "CTNNB1", "mutation", "have", "escaped", "detection.", "However,", "all", "58", "hMLH1", "deficient", "samples", "were", "analysed", "by", "direct", "sequencing", "without", "a", "prior", "screening", "step,", "and", "only", "three", "of", "these", "tumours", "sporadic", " ", "colorectal", "cancer", "cases", "were", "investigated.", "The", "occurrence", "of", "mutations", "in", "the", "CTNNB1", "gene,", "which", "codes", "for", "β-catenin,", "was", "rare:", "only", "five", "of", "464", "tumours", "analysed", "were", "found", "to", "have", "a", "mutation", "at", "one", "of", "the", "phosphorylation", "sites", "in", "exon", "3.", "Truncating", "mutations", "in", "APC", "and", "activating", "mutations", "in", "K-ras", "appeared", "to", "occur", "at", "similar", "frequencies.", "Although", "tumours", "harbouring", "both", "mutations", "were", "relatively", "rare,", "mutations", "in", "APC", "and", "K-ras", "seemed", "to", "occur", "co-dependently.", "Nine", "percent", "of", "all", "tumours", "(58/656)", "lacked", "hMLH1", "expression,", "and", "in", "these", "tumours", "almost", "no", "APC", "or", "K-ras", "mutations", "was", "detected.", "Patients", "harbouring", "a", "tumour", "with", "absent", "hMLH1", "expression", "were", "older,", "more", "often", "women,", "more", "often", "had", "proximal", "colon", "tumours", "that", "showed", "poorer", "differentiation", "when", "compared", "to", "patients", "who", "harboured", "a", "tumour", "with", "an", "APC", "and/or", "K-ras", "mutation." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 12, 12, 9, 17, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Mutations in exon 3 of the CTNNB1 gene leading to loss of one of the phosphorylation sites were rare. Strikingly, all five of these mutations occurred in the proximal colon and three of these also had absent hMLH1 expression. This may indicate that these proximal colon tumours, which often also show mismatch repair deficiency, are more likely to harbour CTNNB1 mutations. This was also found in a study of microsatellite instable colorectal tumours [26]. The WAVE screening technique has not been used previously for formalin-fixed, paraffin-embedded tissue, and therefore it seems plausible that samples harbouring a CTNNB1 mutation have escaped detection. However, all 58 hMLH1 deficient samples were analysed by direct sequencing without a prior screening step, and only three of these tumours sporadic colorectal cancer cases were investigated. The occurrence of mutations in the CTNNB1 gene, which codes for β-catenin, was rare: only five of 464 tumours analysed were found to have a mutation at one of the phosphorylation sites in exon 3. Truncating mutations in APC and activating mutations in K-ras appeared to occur at similar frequencies. Although tumours harbouring both mutations were relatively rare, mutations in APC and K-ras seemed to occur co-dependently. Nine percent of all tumours (58/656) lacked hMLH1 expression, and in these tumours almost no APC or K-ras mutations was detected. Patients harbouring a tumour with absent hMLH1 expression were older, more often women, more often had proximal colon tumours that showed poorer differentiation when compared to patients who harboured a tumour with an APC and/or K-ras mutation.
1266026-05-Discussion-p01
[ "In", "agreement", "with", "prior", "studies,", "there", "were", "seven", "mutations", "estimated", "for", "sporadic", "MSI-", "Finnish", "cancers", "[4],", "and", "seven", "or", "eight", "mutations", "for", "MSI+", "cancers.", "A", "requirement", "for", "more", "alterations", "before", "tranformation", "for", "sporadic", "MSI+", "compared", "to", "sporadic", "MSI-", "cancers", "may", "help", "explain", "why", "sporadic", "cancers", " ", "of", "a", "given", "type", "require", "the", "same", "number", "of", "oncogenic", "mutations,", "but", "stochastic", "differences", "in", "the", "times", "to", "accumulate", "these", "mutations", "allow", "individual", "cancers", "to", "appear", "at", "different", "ages.", "Precisely", "when", "and", "how", "quickly", "mutations", "accumulate", "are", "unknown,", "but", "a", "basic", "premise", "is", "that", "cancer", "types", "requiring", "more", "mutations", "will", "tend", "to", "appear", "later", "in", "life.", "Therefore,", "numbers", "of", "mutations", "may", "be", "estimated", "from", "cancer", "epidemiology.", "Colorectal", "cancer", "frequencies", "increase", "with", "age,", "and", "the", "pattern", "of", "this", "increase", "is", "consistent", "with", "approximately", "five", "to", "seven", "oncogenic", "mutations", "[3-6]." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 17, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
In agreement with prior studies, there were seven mutations estimated for sporadic MSI- Finnish cancers [4], and seven or eight mutations for MSI+ cancers. A requirement for more alterations before tranformation for sporadic MSI+ compared to sporadic MSI- cancers may help explain why sporadic cancers of a given type require the same number of oncogenic mutations, but stochastic differences in the times to accumulate these mutations allow individual cancers to appear at different ages. Precisely when and how quickly mutations accumulate are unknown, but a basic premise is that cancer types requiring more mutations will tend to appear later in life. Therefore, numbers of mutations may be estimated from cancer epidemiology. Colorectal cancer frequencies increase with age, and the pattern of this increase is consistent with approximately five to seven oncogenic mutations [3-6].
1619718-05-Discussion-p03
[ "Concept", "of", "discrete", "colorectal", "lesions", "and", "progression", "to", "colorectal", "cancer", "via", "independent", "pathways" ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Concept of discrete colorectal lesions and progression to colorectal cancer via independent pathways
End of preview. Expand in Dataset Viewer.

Dataset Card for "Variome_split_0404_dev"

More Information needed

Downloads last month
0
Edit dataset card
Size of downloaded dataset files:
1.72 MB
Size of the auto-converted Parquet files:
1.72 MB
Number of rows:
4,801