bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B52: Identification of genes involved in early stage bladder cancer progression.
Authors: Stone Randolph , Sabichi Anita , Gill Jennifer , Lee I-Ling , Loganantharaj Raja , Cvek Urska , Trutschl Marjan , Clifford John
Published: May 2012

B52

Transitional cell carcinoma of the bladder (TCC) ranks 4th in incidence of all cancers in the developed world, yet the mechanisms of its origin and progression remain poorly understood. There are also few useful diagnostic or prognostic biomarkers for this disease. We have combined a transgenic mouse model for invasive bladder cancer (UPII-SV40T mice) with DNA microarray technology, in order to determine molecular mechanisms involved in early TCC development and to identify new biomarkers for detection, diagnosis and prognosis of TCC. We have identified genes that are differentially expressed between the bladders of UPII-SV40T mice and their age-matched wild type (WT) littermates at 3, 6, 20 and 30 weeks of age. These are times which correspond to premalignant, carcinoma in-situ, and early and later stage papillary TCC, respectively. There were approximately 1,900 unique genes differentially expressed (≥ 3-fold difference at one or more time points) between WT and UPII-SV40T urothelium during the time course of tumor development. Among these, there were a high proportion of cell cycle regulatory genes and cytokinesis genes that are more strongly expressed in the UPII-SV40T bladder urothelium. We have tested several of the genes upregulated in UPII-SV40T urothelium, including autocrine motility factor (AMFR), Caspase 3, Cox-2, PCNA and others as biomarkers for premalignancy in urine samples from a completed chemoprevention trial. These results will be discussed in the context of the UPII-SV40T model.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B52.
Abstract B59: Magnetic resonance imaging monitoring of tumor promotion and tumor progression in mouse model of inflammation-promoted colon cancer
Authors: Young Matthew , Ileva Lilia , Riffle Lisa , Bernardo Marcelino , Jones Yava , Kim Young , Choyke Peter , Colburn Nancy
Published: May 2012

B59

Purpose

Early detection of pre-cancerous tissue has significantly increased survival for most cancers including colorectal cancer. Animal models that follow early stages of cancer are valuable for identifying molecular events and response indicators that correlate with the early stages of tumor development. The goal of this work was to generate new methods to monitor over time the early stages of colorectal cancer in mice using magnetic resonance imaging (MRI).

Experimental Design

Mice treated with azoxymethane and dextran sulafate sodium (DSS) were imaged by MRI throughout the tumor development. Early inflammation was imaged in T2-weighted MRI. Dark-lumen images were obtained in both T1 and T2-weighted images using a poly-fluorinated liquid enema. Individual tumor volumes were calculated and validated ex vivo.

Results

Using T2-weighted MRI, inflammation was detected 3 days after DSS exposure and subsided over the next week. The poly-fluorinated liquid enema distended the colon and provided a clear differentiation of the lumen of the colon from the mucosal lining. Tumors were detected as early as 29 days after initiation and as small as 1.2 mm3. Individual tumor growths were followed over time and tumor volumes measured by MRI correlated with volumes measured ex vivo.

Conclusions

Early detection of tumorigenesis is important for understanding tumor development. The use of MRI for detection of the initial stages of colon cancer allows real time evaluation of preclinical trials for prevention and intervention. The use of the poly-fluorinated liquid enema for Dark-lumen MRI in both T1 and T2-weighted imaging could simplify clinical MRI detection of colon cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B59.
Abstract B60: Ultrasound microcalcification does not indicate psammoma bodies in thyroid nodules
Authors: Gamboa-Dominguez Armando , Tinoco-Ventura Erendi , Bezaury Paulina , Rivera-Moscoso Raul
Published: May 2012

B60

Background

The increasing incidence of thyroid nodules is associated with high resolution ultrasound (US) use. Thyroid nodules with irregular margins, vascular spots and microcalcifications in the US analysis have been described as malignant, and no fine needle aspiration (FNA) biopsy is suggested in some centers. It is thought that psammoma bodies, -a very specific finding of papillary thyroid carcinoma- within a nodule, produce the US microcalcifications.The aim of the present study is to identify if psammoma bodies are the source of the ultrasonographic microcalcifications.

Methods

Consecutive US performed in patients with thyroid nodules seen at the thyroid clinic between May 2007 and May 2008 were assessed to identify microcalcifications, margins and vasculature. Cases submitted to thyroidectomy were grossly sampled in suspected zones. Specimens were fixed in buffered formalin, embedded in paraffin and stained with haematoxylin and eosin for histological study. A systematic search for psammoma bodies, dystrophic/non dystrophic small and large calcifications was performed and a histological diagnosis was rendered. Correlation of US microcalcifications and the type of calcification in the different morphological categories was performed. Evaluators were blind and sampling was standardized according to nodule size.

Results

Fifty four patients were included (papillary carcinoma 35, goiter 16, adenoma, Hashimitos thyroiditis and anaplastic carcinoma 1 each). Morphologic analysis depicted psammoma bodies only in papillary carcinoma but also macro calcifications (29%), dystrophic micro calcifications (34%) and Monckeberg vascular calcifications (26%). Macro calcifications were evenly distributed between papillary carcinoma and goiter. No calcifications were identified in 30% of US interpreted as having microcalcifications.

Conclusion

Micro calcifications observed in US are not specific of psammoma bodies or malignancy. A careful interpretation of US micro calcifications is mandatory in thyroid nodule screenings.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B60.
Abstract B61: Modulation of antioxidant gene expression by a fruit juice rich in polyphenols: an intervention study with hemodialysis patients
Authors: Janzowski Christine , Soyalan Bulent , Albert Franz , Rath Thomas , Dietrich Helmut , Will Frank , Eisenbrand Gerhard
Published: May 2012

B61

Patients with chronic renal failure undergoing hemodialysis (HD) face an elevated risk for cancer, artheriosclerosis and other diseases. Factors considered to contribute to such increased health risks include oxidative stress exerted in several ways by the extracorporal blood circuit, but also malnutrition and iron supplementation. A red fruit juice with especially high flavonoid/ polyphenol content previously has been found by us to diminish oxidative cell damage in healthy probands (Weisel et al. Biotechnol. J., 1, 388, 2006). In HD-patients this juice was highly effective as well: In a ten week intervention study with 21 subjects (three week run-in phase (R), four week 200 ml/d juice-uptake (J), three week wash-out phase (W), weekly blood samplings) markedly reduced DNA oxidation damage, protein oxidation, lipid peroxidation and NFκB-DNA binding activity were observed concomitant with significantly elevated glutathione level/status in blood (Spormann et al., Arch. Pharmacol.; 375, 1, 95, 2007).

To evaluate effects on antioxidant genes in a subset of the HD-patients, RNA was isolated from lymphocytes obtained from the blood samplings and gene expression measured by Real-Time TaqMan PCR. Target genes studied where γ-glutamate-cysteine ligase (γ-GCl, catalytic, GCLC and modulatory, GCLM subunits); encoding the enzyme which catalyzes the rate limiting step of glutathione synthesis, glutathione peroxidase 1 (GPX1), glutathione reductase (GSR) and the transcription factor Nrf2 (NF-E2-related factor 2). NFκB regulated cycloxygenase 2 (Cox-2), which plays a pivotal role in inflammatory processes, was also included. Results obtained from 11 patients show a significant induction of both γ-GCL subunits during juice uptake. In the subsequent wash-out phase, GCLC transcription decreased, whereas transcription of GCLM remained elevated. Distinct juice dependent induction of GPX1 and Nrf2 gene expression was also observed, whereas GSR transcription was at best slightly elevated. For Cox-2, the results show a depletion of mRNA transcripts during juice uptake.

In conclusion, the juice intervention clearly lead to elevated transcription of antioxidant genes, reduction of oxidative damage and an increase of antioxidant defense in HD-patients. This provides promising perspectives into prevention of cancer and other diseases in population subgroups exposed to enhanced oxidative stress.

(Supported by Karin Nolte Foundation)

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B61.
Abstract B63: VKORC1 haplotypes influence serum PIVKAII and transaminases levels in hepatocellular carcinoma patients
Authors: Luo Fang , Wang Yibo , Zheng Yi , Fan Xiaohan , Chen Jinxing , Zhang Yu , Hui Rutai
Published: May 2012

B63

Background

VKORC1 haplotypes influence VKORC1 expression and vitamin K-dependent proteins. PIVKAII, named des-γ-carboxy prothrombin, can be used for detecting hepatocellular carcinoma (HCC), and vitamin K deficiency would be associated with low values of serum aspartate transaminase. Whether VKORC1 haplotypes may influence PIVKAII in detecting HCC and serum transaminase?

Methods

A number of measures were compared between patients with different VKORC1 haplotype in 228 HCC patients. VKORC1 haplotypes impact on PIVKAII in detecting HCC was detected in 76 HCC patients and 86 controls. Spearman correlation was used to assess the correlation. Youden's index and positive likelihood ratio were used to weigh the proper concentration of PIVKAII for HCC’s prognosis.

Results

In 228 HCC patients, the genotype-frequencies were similar with Chinese common frequencies, while serum PIVKAII and transaminases levels were significantly higher in CC/CT carriers than those in TT carriers. Both in cases and controls, serum PIVKAII levels were significantly higher in SNP2255-CC/CT carriers than those in TT carriers. The estimated optimal cut-off value of PIVKAII for detecting HCC was 2.0ng/ml and 3.0ng/ml in CC/CT carriers and in TT carriers, respectively.

Conclusions

VKORC1 haplotypes could be a complementary to PIVKAII in detecting HCC, and are associated with serum transaminases levels in HCC patients.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B63.
Abstract B65: Atypia in ductal lavage: A reproducible marker of risk?
Authors: Casano Ashley , Tondre Julianne , Mills Dixie , Love Susan
Published: May 2012

B65

Background

The majority of breast cancers originate in the ductal epithelium of the breast. Ductal lavage provides a minimally invasive tool for assessing epithelial cells and their microenvironment. Previous studies of pathological atypical hyperplasia on biopsy, and cytological aypia in nipple aspirate fluid (NAF) and random fine needle aspiration (FNA) have suggested that these cells are precancerous because of the subsequent increased risk of cancer. It has therefore been hypothesized that serial ductal lavage could be used to identify atypia and monitor the effects of chemoprevention over time. This report is part of a larger study examining the differences in hormone levels and cytology between ducts and their reproducibility. This report presents a cohort of women unselected for risk who voluntarily underwent ductal lavage of the same ducts on two occasions six months apart. Samples were analyzed for epithelial cells and macrophages.

Methods

A total of 107 women were recruited in this IRB-approved prospective study to undergo ductal lavage of three fluid or non-fluid-yielding ducts within a breast. Women were unselected for risk: the average Gail score was 1.67 and ten women had a history of contralateral breast cancer. The average age was 51 years. Fifty-four women were premenopausal, 4 were perimenopausal and 49 were postmenopausal. Samples were submitted in a blinded fashion to a central laboratory and were analyzed by duct for both macrophage and epithelial cell number on Papanicolaou-stained slides. If adequate epithelial cells were present (>10), a diagnosis of each duct (benign, mild atypia, or marked aytpia) was made by an experienced cytopathologist.

Results

Of the 107 women, 317 (99%) ducts were successfully cannulated without regard to nipple aspirate fluid (NAF) production. Thirty ducts in 23 women were diagnosed with mild or marked atypia on either of the two visits. Of these ducts, 16 were diagnosed at the initial visit and 13 at the second visit. Only one duct was diagnosed with mild atypia on both visits, in a woman with a Gail score of 1.4. Cellular atypia in ductal lavage was not reproducible at a six month interval (p=0.45). This absence of reproducibility was seen in women at all risk levels. Macrophage and epithelial cell numbers also showed a lack of reproducibility at the six month interval (p=0.31 and p=0.22, respectively).

Conclusion

Atypia on cytology in ductal lavage in women unselected for risk was not reproducible at a six month interval, suggesting that a single diagnosis of atypia on lavage should not be used as a marker for the identification of women at risk. Further studies are necessary to indicate whether persistent atypia over an extended interval could represent an elevated risk for breast cancer. In addition, ongoing studies are being performed to identify better cellular markers of premalignancy and subsequent risk.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B65.
Abstract B71: Decreased expression of Tgfβ family members appears to be an acquired phenotype of progression to malignancy in the context of loss of Brca1 in mammary epithelial cells.
Authors: Assefnia Shahin , Mitchell Shermaine , Furth Priscilla
Published: May 2012

B71

Rational

Loss of full length Brca1 in mammary epithelial cells of conditional knockout mice is associated with an aberrant proliferative response to estrogen treatment promoting cancer progression. We had previously found that loss of full-length Brca1 in mammary epithelial cells was associated with decreased expression of Tgfβ family members at early stage of malignancy. Initial time course study was conducted to find if decreased expression of growth inhibitory Tgfβ family members is directly related to loss of Brca1 in mammary epithelial cells.

Methods

Mammary gland tissue of Brca1f/f;MMTV-Cre and control wild-type mice from different time points: prior to puberty (age 2½ weeks), mid-puberty (age 6 weeks), end of puberty (age 10 weeks) and maturity (4 and 6 months) was isolated at the time of necropsy(N=3 per cohort). RNA expression levels of TGF-β 1,2,3 and TGF-βRI, II were measured by real time RT-PCR.

Results

No significant differences in the expression levels of Tgfβ family members between Brca1f/f;MMTV-Cre and wild-type mice were found at these time-points using current number of samples.

Conclusions

Decreased expression of Tgfβ family members in these mice does not seem to be directly associated with loss of Brca1 in mammary epithelial cells and appears to be an acquired phenotype as part of the malignancy progression, which would suggest that it is due to modulation of other signaling pathways.

Funding: This study was supported by U.S. Army Medical Research and Material Command WX81XWH-07-1-0588(S. A. and P. A. F.) and Bridges to the Doctorate NIGMS 1R25GM075360-01(S. K. M.).

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B71.
Abstract B77: Translational effects of alternative NAT1 mRNA isoforms
Authors: Millner Lori , Barker David , Howarth Ashley , Doll Mark , States J. Christopher , Hein David
Published: May 2012

B77

N-acetyltransferase 1 (NAT1) catalyzes the N-acetylation of many aromatic amine carcinogens such as 2-aminofluorene and 4-aminobiphenyl. Following N-oxidation by cytochrome P450’s, NAT1 catalyzes the O-acetylation of the N-hydroxy metabolites of many aromatic and heterocyclic amine carcinogens. NAT1 genetic polymorphisms have been associated with differential risks to various cancers related to aromatic and heterocyclic amine carcinogens, but the findings have been inconsistent. Individual susceptibility to these carcinogenic compounds could be modified by genetic polymorphism or by other factors causing differences in NAT1 expression. Our laboratory and others have reported that NAT1 is transcribed from a major promoter, NATb, and an alternative promoter, NATa, resulting in mRNAs with distinct 5’-UTR regions. The 117 nucleotide NATb 5’-UTR contains two noncoding exons, while the 371 nucleotide NATa 5’UTR contains four noncoding exons. The two 5’UTRs share a 79 nucleotide exon immediately upstream of the open reading frame (ORF). We hypothesized that mRNAs including either the NATa or NATb 5’-UTR may be associated with differences in protein expression and that SNPs included in variant NAT1 alleles may modify this effect. We therefore investigated effects on protein expression due to interaction of the different 5’-UTRs with the ORF and region 3’ to the ORF of the reference NAT1*4 allele, and two variant alleles: NAT1*10 and NAT1*11 that are associated with modified risk to arylamine-induced cancers. pcDNA5/FRT plasmid constructs were prepared for transient transfection of full length human mRNAs including either the NATa or NATb 5’-UTR, the ORF, and 885 nucleotides of the region 3’ to the ORF. For each allele of interest, two constructs were made, one including the NATa 5’-UTR and one including the NATb 5’-UTR. Following transient transfection into Chinese hamster ovary cells, NAT1-catalyzed N-acetylation of p-aminobenzoic was measured by HPLC and NAT1 protein expression was measured by Western blot. A difference of approximately 10 fold (p<0.05) in both NAT1 catalytic activity and protein was observed between the NATa and NATb mRNA forms but there was no evidence for allele specific 5’-UTR interactions. These results suggest that differences in NAT1 expression are modified by factors other than polymorphisms in the ORF. Further experiments to examine the possible roles of mRNA production, mRNA stability or differences in mRNA translation efficiency on NAT1 expression are needed. Partially supported by USPHS grants CA034627, ES014559, ES011564, and ES014443.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B77.
Abstract B82: First report of genotype F and novel mutations in the core promoter region of HBV isolates from a northern Indian population
Authors: Singh Jasbir , Pahal Vikas , Kumar Rajesh
Published: May 2012

B82

Hepatitis B virus (HBV) isolates (35) from North India having different stages of hepatitis were studied for genotypes distribution, core promoter mutations and phylogenetic origin. Assays of SGOT, SGPT and HBeAg were performed in all samples using commercial available kits. Genotypes were determined in all the studied subjects by restriction fragment length polymorphism and core promoter mutations by direct sequencing of PCR products. HBV genotype D was found in 57% of the isolates while 40 % isolates have genotype A and 3% have genotype F. This is the first report of genotype F in Indian population. Earlier it was reported from population from Japan, USA, Argenita and Venezuela. Subgenotype D 1 was predominant among genotype D isolates followed by genotype D2 and D6. Subgenotype A1 was predominant among genotype A followed by A3. Genotype F has subgenotype F2. 1762A -T and 1764G-A mutations were observed in 50% isolates having active viral replication of HBV virus. These are also present in the sera of HCC patients. Wild types were observed in many asymptomatic patients. Novel mutations like 1697G 1698C1727A 1740T were observed in the 50% isolates having nearly normal or slightly high ALT/AST level and all the samples were positive for HBeAg. 1811C 1812C1813T mutations were observed in 15% isolates with slightly high ALT/AST level. 1858T was observed in genotype D with HBeAg positive. 1898A stop codon mutations responsible for HBeAg negativity as observed in Japanese, South African and other world populations could not be observed in the isolates under study. Phylogenetic tree of HBV isolates based on the precore/core gene sequences was drawn with HBV sequences from other parts of the world and previously reported Indian strains from eastern part. Majority of strains shows a high degree of closeness with Chinese and eastern Indian strains. Two rare sequences having nearly 46% and 26% difference in the nucleotide sequence with the available wild type with respect to the CP region were also observed. Efforts are going on to amplify the genotype F to full length. The studies regarding mutations, their role in disease progression and potential as biomarkers of hepatitis B is actively underway.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B82.
Abstract B85: Comparison of three oxidative stress biomarkers in a sample of healthy adults
Authors: Watters Joanne , Satia Jessie , da Costa Kerry-Ann , Boysen Gunnar , Collins Leonard , Morrow Jason , Milne Ginger , Swenberg James
Published: May 2012

B85

Oxidative stress is a potentially important etiologic factor for many chronic diseases, including cardiovascular disease, neurodegenerative disease, and cancer, yet studies often find inconsistent results. Three of the most widely-used biomarkers of oxidative stress are F2-isoprostanes for lipid peroxidation and 8-hydroxy-2-deoxyguanosine (8-oxo-dG) and the comet assay with FPG for oxidative DNA damage. The aim of this study was to examine associations among three biomarkers of oxidative stress, F2-isoprostanes, 8-oxo-dG, and the comet assay with FPG, in a sample of 135 healthy African American and White adults. The strongest associations were observed between F2-isoprostanes and the Comet tail moment (r=0.22, p=0.01). There were non-statistically significant weak correlations between 8-oxo-dG and the comet assay (r= -0.09), as well as F2-IsoP (r= -0.04). There were also significant differences between the oxidative stress assessment methods by several participant characteristics, including sex, race, physical activity, and passive cigarette smoke exposure. The results of our study are informative, particularly for researchers seeking to compare results pertaining to oxidative stress across studies and/or assessment methods. The development and use of oxidative stress biomarkers is an exciting and promising field, however additional validation studies are necessary to establish accuracy and comparability across studies and oxidative stress assessment markers.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B85.
Abstract B86: Antioxidant enzymes status in carcinoma cervix patients before and after radiotherapy.
Authors: Sharma Nidhi , Kumar Ashok , Chougle Arun
Published: May 2012

B86

Background and Objectives

Cancer is defined as a cellular growth due to uncontrolled cell division. This involves protein synthesis triggered by unusual acceleration of the process of translation, transcription and replication. The extent of free radical induced oxidative stress can be exacerbated by the decreased efficiency of antioxidant defense mechanisms. Low levels of essential antioxidants in the circulation have been found to be associated with an increased risk of cancer. Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) are the major antioxidant enzymes present in the human body that protect against the oxygen toxicity. Oxidative stress may be a consequence of reduced efficiency of these endogenous antioxidants that may render carcinoma cervix patients more vulnerable to oxidative stress. There are reports suggesting a decrease in SOD and other antioxidant enzymes activities and increase in various markers of lipid peroxidation in carcinoma cervix patients.

Methods

We have undertaken this study to ascertain the possibility of oxidative damage in carcinoma cervix patients by measuring the cytosolic antioxidant enzymes viz., superoxide dismutase (SOD), catalase (CAT), Glutathione (GSH) and lipid peroxidation as well as lactate dehydrogenase levels in circulation of women with cervical carcinoma prior to radiotherapy and at the end of therapy (60~70 Gy tumor dose) in II, IIIA and IIIB and to compare our findings with age matched controls.

Results

In the present study significant decrease (P<0.05) was observed in SOD, CAT, GSH and significantly high plasma lipid peroxide levels and lactate dehydrogenase levels were observed in carcinoma cervix patients when compared to the normal subjects.

Interpretation and Conclusion

Antioxidants play a significant role in the aetiology of human cancer.Result of the present study showed involvement of oxidative stress as one of the risk factors, which can be co-related with the severity of the disease,furthermore these biochemical tests has got excellent prognostic significance

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B86.
Abstract B87: A study of tobacco exposure and oxidative stress related biomarkers in oral cancer
Authors: Patel Jayendrakumar , Shukla Shilin , Shah Pankaj , Patel Prabhudas
Published: May 2012

B87

Objective

Oral cancer is the leading malignancy in India, with tobacco playing a major role in the etiology. The aims of the present study was (i) to assess tobacco exposure related biomarkers in controls, patients with oral precancers (OPC) and oral cancer patients, (ii) evaluate nitric oxide [as NO2+NO3] and antioxidant enzymes in the subjects and (iii) to evaluate correlation between tobacco exposure and oxidative stress related biomarkers in oral cancer patients.

Materials and Methods

Healthy individuals (n=90) were grouped into without habit of tobacco (NHT, n=30) and healthy individuals with habit of tobacco (WHT, n=60). Oral cancer patients with a tobacco habit were classified into abstinence (n=62) and non-abstinence (n=64) groups according to status of tobacco habits at the study time. Urinary nicotine and cotinine levels were analyzed by HPLC using a UV detector. Plasma NO2+NO3, superoxide dismutase (SOD) and catalase levels were estimated by spectrophotometry.

Results

The Odds Ratio (OR) analysis indicated positive associations of both smoking and chewing habits of tobacco with high risk of development of oral cancer. Urinary nicotine and cotinine were significantly elevated in WHT, patients with OPC and oral cancer patients as compared with the NHT group. Levels of urinary nicotine and cotinine were also higher in the non-abstinence group with oral cancers than abstinence group. Mean plasma NO2+NO3 levels were elevated in patients with OPC and oral cancer patients as compared to the controls. Erythrocyte SOD and catalase levels were higher in WHT and patients with OPC as compared to NHT. The erythrocyte SOD and catalase activities were lower in oral cancer patients than patients with OPC. Person’s correlation analysis revealed that the changes in erythrocyte SOD and catalase activities were positively associated with urinary nicotine values. The alterations in plasma NO2+NO3 levels were negatively associated with changes in erythrocyte SOD activities.

Conclusion

The results confirmed that (i) tobacco chewing and smoking habits are prominent risk factors for development of oral cancer in the western part of India (Gujarat). (ii)Urinary nicotine and cotinine levels can be helpful for screening programs for oral cancer. (iii) The alterations in antioxidant activities were associated with production of nitric oxide in oral cancer, which may have significant role in oral carcinogenesis.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B87.
Abstract B90: Genomic loss of a microRNA leads to overexpression of EZH2 in cancer
Authors: Cao Qi , Varambally Sooryanarayana , Mani Ram-Shankar , Shankar Sunita , Wang Xiaosong , Ateeq Bushra , Laxman Bharathi , Brenner J. Chad , Kim Jung , Cao Xuhong , Han Bo , Kumar-Sinha Chandan , Tan Patrick , Palanisamy Nallasivam , Lonigro Robert , Maher Christopher , Chinnaiyan Arul
Published: May 2012

B90

Enhancer of zeste homolog 2 (EZH2), is a histone methyltransferase involved in epigenetic silencing of target genes and plays a central role in regulating embryonic stem cells, metastasis, and cancer survival. EZH2 is overexpressed in aggressive solid tumors and has been shown to function as an oncogene, however, the mechanism of its elevation in cancer is unclear. Here, we identified that a microRNA is a tumor suppressor that inhibits EZH2 expression and function. In contrast to EZH2, this microRNA expression is decreased during prostate cancer progression. Importantly, the genomic loci of this microRNA are somatically lost in prostate cancer as well as in other cancers. Taken together, this suggests a model in which genomic loss of a microRNA in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways resulting in cancer progression and metastasis.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B90.
Abstract CN01-01: Genetic and epigenetic changes in prostate cancer as targets for prevention
Authors: Nelson William , Haffner Michael , Speed Traci , Lee Byron , Yegnasubramanian Srinivasan
Published: May 2012

CN01-01

Prostate cancer cells are known to carry a variety of genetic defects, including gene translocations (eg. TMPRSS-ERG1), amplifications (eg. AR), mutations, and deletions. These changes are thought to endow the prostate cancer cells with new capabilities for dysregulated proliferation, inappropriate survival, tissue invasion and destruction, immune system evasion, and metastasis. In addition, cancer cells also carry epigenetic defects, manifest as changes in CpG dinucleotide methylation patterns and in chromatin structure and organization (eg. at GSTP1 and many others), which are equivalent to genetic changes in promoting malignant phenotypes. During the pathogenesis of prostate cancer, the somatic epigenetic alterations tend appear earlier during cancer development than genetic changes, as well as more commonly and consistently. For this presentation, new data concerning the mechanism(s) by which androgen action might promote translocations at AR target genes, and by which inflammatory processes might trigger CpG island hypermethylation, in prostate cells will be presented. These new insights into the formation of somatic genetic and epigenetic changes will provide new molecular biomarkers to aid in prostate cancer detection and diagnosis, and may lead to new opportunities for prostate cancer prevention and treatment.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN01-01.
Abstract CN02-03: Prospects for targeted reduction of ovarian cancer risk
Authors: Johnson Karen
Published: May 2012

CN02-03

The 5 year survival for patients diagnosed with Stage 3 and 4 epithelial ovarian cancer (EOC) is less than 40% in spite of overall benefit from primary treatment with debulking surgery and chemotherapy. For advanced EOC, even clinical complete responses are usually time-limited, a situation that supports a strategy for earlier intervention. Efforts to establish a screening program with ultrasound and CA-125 have been encumbered by false positive results. The absence of demonstrated benefit in a definitive trial precludes the implementation of widespread screening in the general population. For high risk women like those with BRCA or HNPCC mutations, prophylactic salpingo-oophorectomy is available for risk reduction. Otherwise, the identification of specific risk markers and precursor lesions in the general population remains a challenging goal for EOC prevention research. Because access to human tissues of interest is limited, many questions about the natural history of EOC remain to be answered, and translational efforts have focused on preclinical models and animal studies. In spite of the difficulties, there are promising leads and methodology that can be pursued to make ovarian cancer risk reduction a broader reality.

From epidemiologic studies, a major result in risk modification is the association of oral contraceptive use with EOC risk reduction. The literature is replete with studies that also link EOC with a variety of other hormonal and reproductive factors. These results have been used to support a number of etiologic hypotheses including risk related to 1) incessant ovulation, 2) gonadotropins, 3) hormones (estrogen/androgen/progesterone, and 4) inflammation. These hypotheses are interrelated and support a systems biology approach that integrates changes in the tumor microenvironment along with changes in the epithelium to identify targeted opportunities for preventive modulation. At this point, the translational research process may be well served by small clinical trials that are carefully designed to reconcile inconsistencies in existing data and to test mechanistic leads from preclinical studies as well as from investigations with therapeutics like bevacizumab and anti-Mullerian hormone. Pathways of interest include those related to aromatase and prostaglandins. With specific targets in mind, biomarker comparison in controls using placebo versus subjects using chemopreventive agents as mechanistic probes should allow an improved definition of risk and response.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN02-03.
Abstract CN04-03: Phase 1b sulindac study for women at high risk for breast cancer
Authors: Thompson Patricia , Vining Donna , May Melissa , Chew Wade , Green Sylvan , Stopeck Alison , Alberts David , Chow H-H.
Published: May 2012

CN04-03

Background

Regular use of non steroidal anti-inflammatory agents (NSAIDs) has been associated with reduced risk of breast cancer. The breast specific activity of each of the numerous NSAID agents and their relative potency to prevent breast cancer remains unknown. Sulindac, a non selective NSAID with pro apoptotic activity is a strong candidate for chemoprevention.

Objective and Methods

To assess concentrations of sulindac and its metabolites as well as their effects on known molecular markers in nipple aspirate fluid (NAF) in 15 subjects receiving 150 mg once daily and 15 subjects receiving 150 mg twice daily sulindac. NAF and serum samples were collected before and after 6 weeks of sulindac dosing.

Results

Sulindac and sulfide were detectable in 57.7% of NAF samples with sulfone detectable in 11.6%. There were no statistically significant differences between sulindac or sulfide levels in NAF by dose. There was a significant positive correlation between NAF sulindac and NAF sulfide levels. NAF 13,14-dihydro-15-keto prostaglandin A2 (PGEM), a stable derivative of prostaglandins, exhibited a non significant trend towards decreased levels (p =0.1). Serum levels of sulindac, but not NAF sulindac, was correlated with a decrease in NAF PGEM levels (p=0.03). The NSAID inducible protein, growth differentiation factor GDF-15, showed a borderline significant trend towards higher levels in NAF in the 300 mg daily group (p = 0.07). Serum CRP levels were decreased with sulindac exposure with the greatest decrease observed among those women with elevated CRP levels at baseline.

Conclusion

Sulindac and its sulfide metabolites partition to the breast and are detectable in NAF. Sulindac exposure was associated with a trend towards reduction in PGEM that was correlated with serum levels of sulindac. GDF-15 levels increased in the high dose group. NAF levels of PGEM and GDF-15 may prove useful as NSAID response biomarkers if for larger efficacy based intervention studies in breast cancer prevention.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN04-03.
Abstract CN06-01: Obesity, physical activity, and colon polyps: Black Women's Health Study
Authors: Adams-Campbell Lucile
Published: May 2012

CN06-01

Incidence and mortality rates of colorectal cancer are higher in African-American women than any other ethnic group in the United States and the disparity may be widening. The obesity epidemic in the United States has disproportionately affected African-American women, with obesity being nearly twice as prevalent in African-Americans as Whites. The causes of these increasing rates of obesity are not well understood, although it is hypothesized to be caused by dietary changes and decreased physical activity in the general population over time. An appreciable body of evidence suggests that leisure-time physical activity reduces the incidence of colon cancer. There is much less evidence on whether physical activity protects against colorectal adenomas, which are thought to be precursors to most colon cancers, although the evidence has been inconsistent. No findings have been reported on the relation of physical activity to the incidence of colorectal polyps in African-American women. We report here on the effect of obesity and physical activity on the incidence of colorectal polyps in the Black Women’s Health Study (BWHS), a large follow-up study of black women in the U.S.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN06-01.
Abstract CN06-03: Pediatric obesity research: a transdisciplinary approach
Authors: Spruijt-Metz Donna
Published: May 2012

CN06-03

Energy balance has been defined as the integrated effects of diet, physical activity, and genetics on growth and body weight over the life course, including links to cancer and other co-morbidities. Pediatric obesity is thus a complex field that involves interactions between psychosocial, environmental, neurobiological and metabolic pathways. To understand what drives obesity and related behaviors in minority at-risk adolescent populations, highly transdisciplinary approaches are therefore required. This talk will cover some approaches that have been successfully used to promote transdisciplinary research in pediatric obesity, some of the problems encountered to transdisciplinary work, and some possible solutions to those problems. Examples will be taken from series of increasingly transdisciplinary studies on pediatric obesity in minority youth. These studies draw from a wide range of disciplines including (but not limited to) biology, cancer and cancer biomarkers, metabolism, psychology, nutrition, exercise physiology, engineering, genetics, geography and entertainment, and represent first steps towards an integrated understanding of determinants and outcomes of pediatric obesity.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN06-03.
Abstract CN07-03: Discriminatory accuracy from Single Nucleotide Polymorphisms in models of absolute breast cancer risk
Authors: Gail Mitchell
Published: May 2012

CN07-03

One purpose for seeking single nucleotide polymorphisms (SNPs) that are associated with disease is to improve models for projecting individualized disease risk. Seven SNPs have recently been confirmed to be associated with breast cancer. I used published estimates of relative risks and allele frequencies to calculate how much these SNPs could improve discriminatory accuracy measured as the area under the receiver operating characteristic curve (AUC). A model with these seven SNPs (AUC = 0.574 ) and a hypothetical model with 14 such SNPs (AUC = 0.604) have less discriminatory accuracy than a model, the National Cancer Institute’s Breast Cancer Risk Assessment Tool (BCRAT), which is based on ages at menarche and at first live birth, family history of breast cancer, and history of breast biopsy examinations (AUC = 0.607). Adding the seven SNPs to BCRAT improved discriminatory accuracy to an AUC of 0.632, which was, however, less than the improvement from adding mammographic density. Thus, these seven SNPs improve the discriminatory accuracy of BCRAT only modestly. I used other criteria to compare BCRAT with a model that added the seven SNPs to BCRAT. These criteria included the proportion of cases in the portion of the population with the highest 90% of risk, the expected losses when using risk models to decide which women should be given a mammogram, and the expected losses when using a risk model to decide which women should take tamoxifen to prevent breast cancer. The seven SNPs provided very little improvement over BCRAT for any of these applications. Hundreds of SNPs would be required to achieve high discriminatory accuracy.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN07-03.
Abstract CN09-03: Current controversies in the viral etiology of cancer
Authors: Engels Eric
Published: May 2012

CN09-03

Viruses are among the proven causes of several cancers and suspected in the etiology of others. Highly sensitive molecular techniques (e.g., polymerase chain reaction [PCR]), which can detect minute amounts of viral nucleic acids in human tumors, are useful in suggesting possible causal associations. Detection of viral DNA or RNA in human tumors, on its face, supports the conclusion that the virus is present in the tumor and may therefore have been instrumental in its development. However, reliance on these methods in recent years has generated controversial results in several instances, and some proposed associations have not withstood the test of time.

There are several reasons why use of these sensitive molecular techniques is insufficient in establishing causal associations between viruses and cancer. First, PCR is widely available but poorly standardized, and the methods sometimes yield false-positive results when applied to tumor tissues. Along these lines, quantitative PCR methods are helpful in distinguishing low-level PCR contamination from biologically relevant infection; in the latter case, one would predict at least one PCR-quantifiable copy of virus per tumor cell. Second, additional laboratory techniques are required to localize viruses within tumor cells, demonstrate expression of key viral oncoproteins, and establish integration into host DNA and clonality of the virus_all of which add important supportive evidence that the virus is present in the tumor and driving proliferation. Third, epidemiologic evidence from population-based studies in humans is required to demonstrate that host infection precedes development of the cancer and that infection is associated with an increased risk of cancer during follow-up. A strong magnitude of association (i.e., a large relative risk relating infection to a sizably increased cancer risk) provides important supportive evidence. These epidemiologic studies require rigorous design and validated measurements of host infection (e.g., assays for systemic antibody production or viremia).

Controversy typically arises when evidence from molecular studies of tumor tissues is not supported by, or actually conflicts, with other lines of evidence. Further controversy can arise from inconsistencies in molecular results within or across laboratories. Several examples will be reviewed, including a recent controversy surrounding the possible role of simian virus 40 in development of several cancers in humans. Investigators must treat initial reports of possible associations between viruses and cancer with caution. Replication of initial findings by independent research groups, and evaluation of the proposed association using several complementary laboratory and epidemiologic approaches, is required to establish a causal relationship.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN09-03.
Abstract CN12-01: Clonal evolution over time in Barrett's Esophagus
Authors: Maley Carlo
Published: May 2012

CN12-01

Our current theory of neoplastic progression specifies that clones arise through genetic or epigenetic instability, and if they have a reproductive or survival advantage over other cells in the neoplasm, within their microenvironment, they will expand in the neoplasm in a selective sweep. Thus, we believe neoplastic progression is characterized by a series of selective sweeps. However, virtually all data on that process to date is cross-sectional, with observations of genetic diversity and large clonal expansions within neoplasms at a single time point. I will describe data that, for the first time, tracks the evolutionary dynamics of clones in a solid neoplasm over time. We have analyzed the frequency of large clonal expansions, the rate of those expansions and changes in clonal diversity over time in a cohort of 174 patients with Barrett’s esophagus. Barrett’s esophagus is a premalignant condition that predisposes to the evolution of esophageal adenocarcinoma. Unlike most other premalignant neoplasms, the Barrett’s tissue is not resected upon detection due to significant mortality and morbidity associated with esophagectomies. Instead, serial endoscopic surveillance for the early detection of cancer is the recommended management of the condition. This allows us to study neoplastic progression over both space and time in unprecedented detail. In the Seattle Barrett’s Esophagus Project, we also gather data on host and environmental factors that may impact progression, including use of non-steroidal anti-inflammatory drugs, which have been associated with a dramatic reduction of risk for progression to cancer. I will relate the factors associated with clonal expansions and genetic diversity to the parameters that determine the rate of evolution: mutation rate, population size, stem cell generation time and the fitness effects of mutations.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN12-01.
Abstract CN12-02: Evolution in carcinogenesis
Authors: Shibata Darryl
Published: May 2012

CN12-02

Histories are inherently recorded within genomes by errors that inevitably occur during replication. Essentially, the greater the number of genome replications, on average the greater the numbers of differences between two genomes (“molecular clock hypothesis”). Recent “cancer genome projects” have revealed how a genome changes during its evolution to colorectal cancer. Interesting findings are the relatively low numbers of somatic mutations (<1 mutation per 100,000 bases), the infrequency of commonly mutated genes (many more “hills” than “mountains”), and marked heterogeneity of mutations between different cancers (overlap of mutated genes was minimal). There was an average of ~80 somatic mutations in genes per cancer, with relatively more “passenger” mutations than “driver” mutations. Greater than 80% of the mutated genes within a cancer genome are thought to be neutral passenger mutations. Relatively normal cell division and mutation rates can account for the numbers of changes in a cancer genome. By counting numbers of somatic changes (mutation and epigenetic changes), it may be possible to reconstruct the mode and tempo of cancer evolution starting from the zygote.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN12-02.