bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk-reducing salpingo-oophorectomy and prophylactic mastectomy among BRCA mutation “previvors.”
Authors: Holman Laura L. , Daniels Molly S , Brandt Amanda C. , Arun Banu , Keeler Elizabeth , Gershenson David Marc , Sun Charlotte C. , Lu Karen H. 
Published: March 2020

1518 Background: We prospectively evaluated the timing and uptake of risk-reducing surgery in a cohort of female BRCA mutation carriers that have no personal cancer history (“previvors”). Methods: Patients at high risk of breast and ovarian cancer were enrolled between 2007 and 2011 and followed in a high-risk ovarian cancer screening clinic. Women were offered risk-reducing salpingo-oophorectomy (RRSO) and/or prophylactic mastectomy (PM) per guidelines. Their clinical data were recorded and analyzed using descriptive statistics. Results: Of 260 BRCA mutation carriers enrolled, 73 have no personal history of cancer and are “previvors.” Patients have been followed for a median of 26.5 months (1-50 months). The median age is 38 years, 81.1% are white, 16.2% are Ashkenazi Jewish, and 79.7% are premenopausal. BRCA1 carriers account for 43.2% of participants and 55.4% have a BRCA2 mutation. The majority of patients (77.6%) presented for ovarian cancer screening <1 year after their BRCA testing. In all, 60.8% of women underwent prophylactic surgery: 28.4% chose RRSO, 18.9% chose PM, and 13.5% chose both procedures. Postmenopausal women were more likely to choose RRSO, while uptake for both procedures was common for premenopausal women (Table, p=0.04). RRSO was also more likely in parous than nulliparous premenopausal women (35.2% vs 9% p=0.001). PM was not associated with parity (p=0.79). Of women that had both surgeries, 20% had them concurrently and 20% had PM first. Of the 60% that underwent RRSO first, all had their second surgery within 14 months. Conclusions: BRCA mutation “previvors” have a high overall uptake of prophylactic surgery. Premenopausal women are more likely to choose PM than postmenopausal women; reasons for this are unclear. “Previvors” that choose RRSO and PM typically have both surgeries within a fairly short timeframe. With the growing population of “previvors” in the US, further study of patient preferences regarding preventative surgery and long-term consequences is needed. [Table: see text]
Breast cancer intrinsic subtypes by PAM50 in older women.
Authors: Jenkins Emily Oldham , Deal Allison Mary , Anders Carey K. , Prat Aleix , Perou Charles M. , Carey Lisa A. , Muss Hyman Bernard 
Published: March 2020

1524 Background: Breast cancer (BC) incidence dramatically increases with age and the number of older BC patients (pts) in the U.S. is rising. Although immunohistochemical (IHC) data confirm that the incidence of luminal BC increases with age while the incidence of triple negative (TN) BC decreases, age-specific data on the frequency of BC subtypes defined by gene expression is limited. We characterized the incidence of BC intrinsic subtypes using gene microarrays according to age. Methods: Data from 2,150 pts were pooled from publicly available microarray datasets to determine the incidence of PAM50 breast cancer intrinsic subtypes (Luminal A [LumA], Luminal B [LumB], HER2-enriched [Her2E], Basal-like [Basal] and Normal-like [Norm]) by age. Adjuvant treatment data (none, chemotherapy, endocrine therapy or both) were available for 1,741 samples. Relapse-free (RFS) and overall survival (OS) differences were determined using the Kaplan-Meier method. Results: PAM50 intrinsic subtypes by age are tabulated below. The incidence of luminal (A, B, A+B) tumors increased with age (p<0.01, p<0.0001, p<0.0001, respectively), while the percentage of basal tumors decreased (p<0.0001). Basal tumors represented 13% of pts aged > 70 years (yrs); of the 70% with available IHC data, 74% were TNBC. Age as a continuous variable was not associated with RFS (p = 0.37). Subtype alone (n=2031), and after controlling for treatment (n=1645), was significantly associated with RFS (both p<0.0001). The addition of age to a multivariate analysis added no prognostic information. Conclusions: Though more favorable subtypes increase with age, older BC pts still have a substantial percentage of high-risk subtypes. Age alone was not a significant factor in outcome. Tumor biology as defined by intrinsic subtype is an important clinical predictor. [Table: see text]
Identification of new susceptibility genes in familial breast cancer by exome sequencing.
Authors: Lynch Henry T. , Wen Hongxiu , Kim Yeong , Snyder Carrie , Kinarsky Yulia , Chen Pei Xian , Cowan Kenneth H. , Goldgar David , Wang San Ming 
Published: March 2020

1538 Background: Familial breast cancer was described in the early 1970s with its syndromy confirmed by the discovery of BRCA germline mutations in the 1990s. BRCA mutations account for less than 10% of affected families. Efforts made in the past two decades have resulted in limited results in identifying additional susceptibility genes for familial breast cancer. Methods: Using exome sequencing, we analyzed eight members in a BRCA1-, BRCA2-, p53- and PTEN-negative breast cancer family; five with breast cancer and three unaffected. Mutation candidates were idenified by bioinformatics analysis, experimentally validated by Sanger sequencing and their damaging effect was predicted by the SIFT program. Validated mutations were also tested in 42 additional breast cancer samples from BRCA-negative breast cancer families. Results: We identified 55 non-synonymous germline mutations affecting 49 genes in multiple members of this family, 20 of 22 selected mutations predicted to cause damaging effects were validated. As an exemplar, two mutations in the MYST4 gene were detected at the C terminal (p.D1516Y and p.R1577C), validated, and predicted to cause damaging consequences. MYST4 is a histone acetyltransferase (Champagne, N. et al. JBC. 274, 28528-28536,1999). It contains a C2HC-type finger and a PHD-type zinc finger. Its N-terminal is involved in transcriptional repression while its C-terminal is involved in transcriptional activation and interacts with important transcriptional regulators RUNX1 and RUNX2. MYST4 is involved in DNA replication, transcriptional regulation, and epigenetic modification of chromatin structure. A translocation t(10;16)(q22;p13) between CREBBP and MYST4 was identified in acute myeloid leukemia. The 20 validated germline mutations were tested by Sanger sequencing in 42 additional breast cancer cases from 26 BRCA-negative families. None of the 20 mutations were detected. Conclusions: Results show that remaining unknown susceptibility genes are likely family-specific and can be detected in each affected family using genome sequencing approaches. These results may be the first reported in an exome sequencing study of BRCA-negative breast cancer families.
Evaluation of genes associated with undescended testes as predictors of TGCT susceptibility.
Authors: Marshall Ariela , Ciosek Stephanie L. , Vardhanabhuti Saran , Mitra Nandita , Vaughn David J. , Kanetsky Peter A. , Nathanson Katharine 
Published: March 2020

1539 Background: Testicular germ cell tumors (TGCTs) are highly heritable. Cryptorchidism (undescended testes; UDT) is a strong risk factor for TGCT, with increased risk to both the ipsilateral and contralateral testes. However, recent genome-wide association studies (GWAS) identifying genetic variants associated with TGCT susceptibility have not found differences in genotype carriage between TGCT patients with and without UDT. We investigated the role of potential risk variants for UDT as risk factors for TGCT. Methods: 1300 SNPs in and around 25 gene regions with published associations with UDT were evaluated in 474 TGCT cases (45 with UDT) and 919 controls. Genotype information was available from the Affymetrix Genome-Wide Human SNP Array 6.0. Statistical analysis was performed using PLINK, and statistical significance was assessed by Fisher's Exact test. Results: Comparing TGCT cases with and without UDT, variants in the region of four genes (EPHB2, ESR1, SEMA3C, TGFBR3) were suggestively associated with UDT. When TGCT cases with UDT were compared with unaffected controls, the associations all met the required level of significance (p < 4 x 10-5). Only variation at ESR1 approached significance (P=0.0004) when TGCT cases and unaffected controls were compared. Conclusions: We identified variants at three genetic loci - SEMA3C, TGFBR3 and EPHB2 - that were significantly associated with UDT, but not with TGCT. The association of variation in EPHB2 and SEMA3C with UDT are novel findings. While associated with UDT, variation at ESR1 is also potentially associated with TGCT risk. These data continue to suggest that genetic risk factors for UDT are largely independent of those for TGCT. Thus, screening for TGCT could be targeted in a UDT population to those with genetic risk factors. Further studies should be done to investigate the genetic link between UDT and TGCT.
Features of familiality in a cohort of patients (pts) with sarcoma.
Authors: Lypas Georgios , Root Elizabeth J. , George Suzanne , Wagner Andrew J. , Butrynski James E. , Morgan Jeffrey A. , Demetri George D. , DiGianni Lisa , Masciari Serena , Rath Michelle Genevieve , Garber Judy Ellen , Raut Chandrajit P. 
Published: March 2020

1547 Background: Sarcomas occur in a number of cancer predisposition syndromes, yet genetic evaluation is rarely recommended for sarcoma pts. We broadly reviewed the family cancer histories of unselected pts in a tertiary center sarcoma clinic to explore the potential relevance of genetic assessment. Methods: Between 2005 and 2008, 397 pts (median age 52 years) with documented sarcoma who consented to research use of medical records and tissues also completed a family history questionnaire. Patient and family histories were reviewed for features suggesting hereditary risk (e.g. early age at diagnosis or familial clustering of certain associated diagnoses). Results: A family history of malignancy was noted in 301 of 397 pts (76%). Seventy-six pts (19%) were diagnosed with 99 additional malignancies, most frequently breast cancer (n=23), prostate cancer (12), melanoma (12), thyroid cancer (6) or a second sarcoma (10). Sarcoma was diagnosed prior to or synchronously (within 6 months) with another malignancy in 20 pts and metachronously in 56 pts. In 18 pts, sarcoma arose within a prior radiation field. Thirty-seven pts (9%) had a sarcoma subtype associated with a recognized syndrome: desmoid fibromatosis (n=16), malignant peripheral nerve sheath tumor (11), PEComa/angiomyolipoma (6), retinoblastoma (3), and GIST with paraganglioma (1). Based on additional features, the associated syndromes were confirmed in 6 of them (1.5% of the cohort): familial adenomatous polyposis (n=1), neurofibromatosis type 1 (2), familial retinoblastoma (2), and Carney-Stratakis dyad (1). Thirty-three pts (8% of the cohort, or 16% of pts age <50) fulfilled TP53 testing criteria (Chompret, Birch or classical Li-Fraumeni Syndrome [LFS] criteria). Another 147 pts (37% of the entire cohort) did not fulfill LFS testing criteria, but were diagnosed with sarcoma before age 50 and had at least one first or second degree relative with a diagnosis of malignancy before age 50. Conclusions: Sarcomas are rare and diverse cancers. Given the potential association with cancer predisposition syndromes, genetic evaluation should be strongly considered in sarcoma pts based on age at diagnosis, histology, and family cancer history.
Ethnic difference of driver mutation frequencies and correlations between driver mutations and histologic subtypes in lung adenocarcinoma.
Authors: Yamane Yuki , Goto Koichi , Kawase Akikazu , Tsuchihara Katsuya , Mimaki Sachiyo , Ishii Genichiro , Ohmatsu Hironobu , Niho Seiji , Yoh Kiyotaka , Umemura Shigeki , Nagai Kanji , Ohe Yuichiro , Ochiai Atsushi , Esumi Hiroyasu 
Published: March 2020

1552 Background: The frequencies of known driver mutation in lung adenocarcinoma from patients in the United States have been reported by the NCI’s Lung Cancer Mutation Consortium (LCMC), indicating driver mutations were detected in 54% (280/516) of tumors. In this report, mutations found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK rearrangements 7%. However little is known about ethnic difference of driver mutation frequencies and correlations between driver mutations and histological subtypes in lung adenocarcinoma. Methods: Known driver mutations in tumors from 97 Japanese patients with lung adenocarcinoma who underwent surgical resection between 1999 and 2003 in National Cancer Center Hospital East were analyzed by next-generation sequencing and confirmed by Sanger sequencing. Correlations between driver mutations and histological subtypes were also assessed. Results: Driver mutations were detected in 72% of tumors. Mutations found: EGFR 57%, KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement detection by exon-sequencing, ALK rearrangements were not analyzed. Compared with the report by LCMC, the frequency of EGFR mutations was high and that of KRAS mutations was low in the present study. All mutations were mutually exclusive. The number of predominant histological subtypes of tumors harbored EGFR mutations were papillary 28, acinar 3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. Two tumors harbored PIK3CA mutations showed both histological acinar pattern. Each of BRAF mutation and MET amplification showed lepidic and papillary pattern, respectively. Conclusions: It was suggested that there should be ethnic difference of driver mutation frequencies in lung adenocarcinoma between Asian and non-Asian patients, although the details of ethnic distribution included in LCMC study has not been opened. In addition, each driver mutations did not correspond to specific histological subtypes of lung adenocarcinoma.
Variants of uncertain significance in BRCA testing: Impact on risk perception, worry, prevention, and counseling.
Authors: Graham Tracy , Eisen Andrea , Richter Sue , Haroun Iman , Warner Ellen 
Published: March 2020

1555 Background: Genetic testing for BRCA1 and BRCA2 is an instrumental tool in clinical decision-making. Variants of uncertain significance (VUS) can occur in up to 25% of individuals and pose clinical challenges. We compared i) result recall ii) risk perception iii) worry and iv) risk modifying behaviours in individuals with VUS, a pathogenic mutation (PM) or an uninformative result (UR). Care provider attitudes to VUS were also studied. Methods: A questionnaire was mailed to women testing positive for a VUS, PM or UR. Items included demographics, time from disclosure, result recall and cancer worry using the validated Trask score. Likelihood of risk modifying behaviours or intensified screening was evaluated by 5 point Likert scale. 9 regional genetic counselors and 11 referring physicians were surveyed on VUS management. Responses were evaluated by chi square and ANOVA. Results: All groups had similar age, marital status and education. Failure to correctly identify a result as uninformative occurred in 32% of VUS; 90% had low economic status. 87% (VUS) and 44% (PMC) had personal history of breast cancer. Perceived risk increased after disclosure in 29% (VUS), 70%(PM) and 10% (UR) (p<0.001). Mean Trask scores were 7.6 (VUS) and 9.8 (PMC) (p=0.006, t-test). In affected patients, mastectomy was 22% (VUS) and 55% (PMC) (p=0.01), oophorectomy 39% (VUS) and 85% (PMCs) (p<0.001) with75% and 95% intensified screening 75% in unaffected VUS and PM (p=0.16). 3% (VUS) and 6% (PMC) agreed with chemoprophylaxis (p=NS). Genetic counselors unanimously reported low comprehension in VUS vs PM. VUS was disclosed only 75% of the time with poor comprehension, perceived anxiety and negative family history as reasons. Referring physicians recommended predictive testing for relatives of VUS carriers (100%). Conclusions: Nearly 1/3 of patients fail to recall their VUS as uninformative. Perceived risk was increased after VUS disclosure but lower than PMC. Worry scores showed impact on daily functioning. Uptake of prophylactic surgery was lower in affected VUS vs PMC carriers with similar rates of intensified screening if unaffected. Patients with low economic status or anxiety are at particular risk of incomplete counseling.
First report on screening an asymptomatic population for cancer: The yield of an integrated cancer prevention center.
Authors: Sella Tal , Boursi Ben , Gat-Charlap Amira , Aroch Ilan , Liberman Eliezer , Moshkowitz Menachem , Miller Ehud , Gur Eyal , Blachar Arye , Mabjeesh Nicola J. , Sperber Fanny , Reiser Vadim , Kleinman Shlomi , Jaffa Ariel J. , Ormianer Mati , Naumov Inna , Kazanov Diana , Kraus Sarah , Galazan Lior , Arber Nadir 
Published: March 2020

1564 Background: Cancer is a leading cause of mortality worldwide. Screening is a key strategy for reducing cancer morbidity and mortality. We aimed to evaluate the utility of cancer screening in an asymptomatic population at an integrated cancer prevention center. Methods: One-thousand consecutive asymptomatic, apparently healthy adults, aged 20-80 years, were screened for early detection of 11 common cancers by routine screening tests. Results: Malignant and benign lesions were found in 2.4% and 7.1% of the screenees, respectively. The most common malignant lesions were in the gastrointestinal tract and breast followed by gynecological and skin. The compliance rate for the different screening procedures was considerably higher than the general Israeli population – 78% compared to 60% for mammography (p<0.001) and 39% compared to 16% for colonoscopy (p<0.001). Advanced age, family history and certain lifestyle parameters were associated with increased risk for cancer. Moreover, polymorphisms in the APC and CD24 genes indicated high cancer risk. When two of the polymorphisms existed in an individual, the risk for a neoplastic lesion was extremely high (OR 2.3 [95% CI 0.94-5.9]). Conclusions: A significant number of neoplastic lesions were diagnosed at an early stage. Polymorphisms in the APC and CD24 genes may identify individuals at an increased risk for cancer. Cancer may be diagnosed at an early stage using the screening facilities of a multidisciplinary outpatient clinic.
Factors and trends in cancer screening in the United States from 2004 to 2010.
Authors: Reungwetwattana Thanyanan , Molina Julian R. , Ziegenfuss Jeanette Y. 
Published: March 2020

1565 Background: Understanding the prevalence of cancer screening in the US and the factors associated with its accessibility is important for public health promotion. Methods: The 2004 and 2010 Behavioral Risk Factor Surveillance Systems were used to ascertain cancer screening rates among populations indicated for each test by age, gender, and the American Cancer Society recommendation for cancer screenings [fecal occult blood test (FOBT) or endoscopy for colorectal cancer (CRC) screening, digital rectal examination (DRE) or prostate specific antigen (PSA) for prostate cancer screening, clinical breast examination (CBE) or mammogram for breast cancer screening, and Papanicolaou (Pap) test for cervical cancer screening]. Results: Over this period, CRC and breast cancer screening rates significantly increased (15.9%, 13.9%) while prostate and cervical cancer screening rates significantly decreased (1.2%, 5.2%). Race/ethnicity might be an influence in CRC and cervical cancer screening accessibility. Prostate cancer screening accessibility might be influenced by education and income. The older-aged populations (70-79, >79) had high prevalence of CRC, prostate and breast cancer screenings even though there is insufficient evidence for the benefits and harms of screenings in the older-aged group. Conclusions: The disparities in age, race/ethnicity, health insurance, education, employment, and income for the accession to cancer screening of the US population have decreased since 2004. The trajectory of increasing rates of CRC and breast cancer screenings should be maintained. To reverse the trend, the causes of the decreased rate of cervical cancer screening and the high rates of screenings in older-aged populations should, however, be further explored. [Table: see text]
Patient perceptions of stool-based DNA testing across racial groups.
Authors: Huang Lily , Chen Zhengyi , Lynn Audrey , Devore Nathan , Nguyen Minh-Tri , Thompson Cheryl L , Cooper Gregory , Markowitz Sanford D. , Li Li 
Published: March 2020

1569 Background: Despite the widespread acceptance of colonoscopy as the gold standard for Colorectal Cancer (CRC) screening, compliance rates with recommended CRC screening lag far behind screening for breast and cervical cancers. Patients often delay or forgo screening colonoscopy due to associated discomfort, inconvenience, anxiety, and high cost. In addition, recent data have casted doubt on its effectiveness, especially in detecting right-sided colon neoplasia. Stool-based DNA (sDNA) testing is an emerging CRC screening tool that is convenient, noninvasive, and effective in detecting both right and left sided colon cancer. The goal of this study was to evaluate patient attitudes towards sDNA testing, identify preferences in CRC screening tools, and assess racial differences in these attitudes and preferences. Methods: In a colonoscopy-based case-control study, 100 patients of average CRC risk were asked to complete (1) sDNA testing (LabCorp ColoSure test), (2) screening colonoscopy, and (3) a patient satisfaction survey. Results: Eighty patients completed the study, including 55 (69%) White, 22 (27%) African American, and 3 (4%) Others. Overall, patients rated sDNA testing favorably in all preparation and test related features, except for perceived accuracy. Patients reporting a preferred screening method favored sDNA testing (78%) to FOBT (12%) or colonoscopy (10%), and 83% of all patients reported that they are likely to repeat sDNA testing. Non-Caucasians rated sDNA testing less favorably than Caucasians – reporting more discomfort (ANOVA, p<0.004), more anxiety (ANOVA, p<0.001), and less suitability (Chi-Squared, p<0.0035). Of those patients reporting a preferred screening test, 82% of Caucasians and 64% of non-Caucasians selected sDNA testing. Conclusions: Although sDNA testing was ranked less favorably by non-Caucasians, it was well received overall as the preferred CRC screening test, as compared to FOBT and colonoscopy. The differences between racial groups may reflect the generally lower uptake of CRC screening among non-Caucasians, regardless of the test. In conclusion, sDNA testing may be an effective means to increase CRC screening in African Americans, hence preventing CRC and closing the racial disparity gap.