Recent Research in Cancer
Adipose Related Biomarkers of Prostate Cancer
Effects of Brassica Intake or Indole-3-Carbinol (I3C) Supplements on PSA among Men with Biochemical Failure
Epidemiology of Molecular Risk Factors for Breast Cancer
Mechanisms and Management of Familial Colorectal Cancer
Nashville Breast Health Study
Nashville Men’s Health Study: Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer
Southern Community Cohort Study (SCCS)
Adipose Related Biomarkers of Prostate Cancer
Adipocytes highly express the GYP19 gene encoding aromatase, an enzyme responsible for metabolizing androgens (e.g., testosterone) to estrogen (E). Estrogens activate estrogen and androgen receptors in prostate cells, and E exposure may permit cancer of the prostate (CaP) to progress to clinical detection and androgen-independence. Recently, a preliminary investigation found the Arg264Cys polymorphism in CYP19 associated with increased CaP risk, suggesting that body adiposity affects prostate carcinogenesis by altering the androgen/estrogen balance. However, epidemiologic studies provide little support for a relationship between obesity and CaP, perhaps because it is difficult to estimate body adiposity in large epidemiologic studies. Our multi-disciplinary team from the fields of nutritional epidemiology, pathology, medical genetics, molecular biology, and urology propose to investigate the role of adipose and estrogen related biomarkers in prostate carcinogenesis. Toward this goal, this pilot molecular epidemiologic study aims to recruit men undergoing confirmatory diagnostic tests for CaP. Fasting blood samples will be collected, and diet, physical activity, body size, and other CaP risk factors will be measured during pretreatment interviews. The recruitment base includes clinical centers serving the African-American population of Nashville, TN. With the endorsement of clinical staff we expect to recruit 70% of all biopsy patients at these centers, providing 250 CaP cases during one year. A control group (n=250), matched to the age and race distribution of the case group, will be selected from men without CaP at biopsy. Bias in the analysis may be reduced by excluding controls with latent CaP, systematic data collection by trained interviewers, and analysis of pre-treatment blood samples. The association between CaP and CYP19 genetic polymorphisms (Arg264Cys, allele length) will be investigated using multivariable logistic regression controlling for genetic susceptibility to adipocyte differentiation (the Pro12Ala polymorphism of peroxisome proliferator activated receptor- y2), body adiposity (blood leptin), insulin resistance (blood insulin and Cpeptide), diet, physical activity, and other potential CaP risk factors. Greater body adiposity may advance prostate carcinogenesis through an estrogen mechanism, and an analysis of adipose-related biomarkers may suggest that weight reduction would decrease CaP risk or improve prognosis. Funded by the National Cancer Institute Investigators: Jay H. Fowke, M.P.H., Ph.D. (PI)
Effects of Brassica Intake or Indole-3-Carbinol (I3C) Supplements on PSA among Men with Biochemical Failure
There is considerable basic science research to suggest that isothiocyanates (ITC) or several indole analogs (e.g., indole-3carbinol (I3C)) slow cellular proliferation, re-instate apoptotic action, and reduce colon tumor incidence. Humans are exposed to these agents primarily through consuming Brassica vegetables (e.g., broccoli), but it is unknown if greater Brassica consumed could affect colon cancer risk. We propose a short-term pilot dietary intervention to investigate the effects of greater Brassica consumption on markers colon cancer progression. Twenty adenoma patients will participate in a randomized controlled cross-over trial. Recruitment, intervention, and lab protocols have been developed through other on-going studies, improving the cost-efficiency of this pilot project. The intervention-arm of the trial is based on a model developed for the Women’s Health Initiative, and provides social support and information to help participants incorporate these vegetables into their daily diet. Biomarkers measured from rectal biopsies will include Bcl-2 (inhibits apoptosis), Bak and Bax (promote apoptosis), Mib-1 (marker of cellular proliferation), and p21 (marker of cellular differentiation). Multiple 24-hour dietary recalls will measure each participant’s adherence to the intervention. Dietary adherence will be measured further by urinary ITC level (combined with GST enzyme genotype), a unique and specific biomarker of Brassica vegetable intake. Using mixed-model repeated-measures ANOVA, we will compare molecular marker expression when participants consume Brassica vegetables to when these same participants consume an over-the-counter fiber and vitamin supplement. This pilot study will provide the needed estimates of variance in biomarker response to the dietary change for sample size calculations for future applications. Previously, we found that healthy people were able to increase the consumption of these vegetables with minimal social and instructional support, and we used those pilot data to gain funding for a larger randomized trial enrolling breast cancer survivors. Since Brassica vegetables are widely available, inexpensive, and consumed without harm, a change in molecular marker expression consistent with reduced proliferation and enhanced differentiation and apoptosis would suggest further research to evaluate the application of Brassica consumption to reduce colon cancer risk. Funded by the National Cancer Institute Investigators: Jay H. Fowke, M.P.H., Ph.D. (PI); Sam Chang, M.D.; Saundra Motley, R.N.
Epidemiology of Molecular Risk Factors for Breast Cancer
We propose to study molecular, genetic and histologic markers of breast cancer risk in women with benign breast disease. We will use a unique cohort of such women to pursue the following Specific Aims: 1. To determine the effects on breast cancer risk of the 6A polymorphism of the transforming growth factor beta type I receptor (T(3R-I). We will also study how expression levels of the TpR-l, and its principal substrate Smad2, affect breast cancer risk in women with proliferative breast lesions. 2. To evaluate the combined influence on breast cancer risk of benign breast lesions and 424 single nucleotide polymorphisms (SNPs) from 86 candidate genes involved in estrogen biosynthesis, function and oxidative metabolism. Cross-sectional analyses will also be performed that examine how specific genotypes are correlated with different types of benign breast disease. These studies will explore potential influences on breast cancer risk of ER-mediated cell proliferation or the generation of oxidative estrogen metabolites that may damage DNA. 3. To expand the size and length of follow-up of our study cohort. The research will be based on a large retrospective cohort study of women who underwent benign breast biopsy between 1954 and 1995. Paraffin-embedded tissue from the entry biopsy of these patients is available. By the end of this project we estimate that we will have observed 890 breast cancer cases during follow-up among the 11,547 members of this cohort. We will conduct a series of nested case- control studies on these women. The 890 breast cancer cases will be matched by race, age and year of their benign breast biopsy to 1780 controls (1:2 ratio). Genotyping will be performed using the Illumina GoldenGate assay while immunohistochemical methods will be used to identify abnormal protein expression. We will use supervised principal component analyses to assess the individual and combined effects of molecular, histologic and epidemiologic variables on breast cancer risk. A false discovery rate (FDR) approach will be used to identify promising findings that will be subject to validation in other data sets. This project takes advantage of an established cohort of women with biopsy-confirmed benign breast disease. Clinical, demographic, and histologic information, as well as genomic DNA is uniformly available. This project will permit the combination of modern methods in molecular biology, genetics, pathology and epidemiology to assess potentially powerful new markers of breast cancer progression and prognosis. We expect that it will lead to important advances in the prevention and treatment of this disease. Funded by the National Cancer Institute Investigators: William Dupont, Ph.D. (PI)
Mechanisms and Management of Familial Colorectal Cancer
Advances in genomics offer the potential for novel clinical applications designed to identify individuals at greater susceptibility to cancer and develop personalized risk-reduction strategies. As such, the family history assessment is becoming increasingly important for cancer control and prevention. While significant advances have been made in our understanding of the etiology and clinical management in inherited colorectal cancer syndromes, such as familial adenomatous polyposis or hereditary non-polyposis colorectal cancer, most individuals with a family history of colorectal cancer do not have one of these well-described, Mendelian conditions. Our understanding of the mechanisms underlying the familial aggregation of colorectal cancers and the most effective screening strategies for individuals at increased risk for colorectal cancer remains limited. The long-term goals of Dr. Murff are to better delineate the complex genetic and environmental factors associated with familial colorectal cancer and translate these findings into improved management of high-risk individuals. The research aims of this proposal include: 1) To determine the effect of a family history of colon cancer on the initiation of colorectal cancer screening interventions; 2) To determine if an interaction exists between having affected relatives with colorectal cancer and patient lifestyle factors on adenoma risk; 3) To evaluate the relationship of functional genetic polymorphisms within the transforming growth factor beta signaling pathway to colonic adenoma risk and family colon cancer history; 4) To determine the cost-effectiveness of colorectal cancer screening in individuals at increased risk based on their family history. The early phases of this career development award will build on the candidate’s prior work and determine current practices for cancer screening in high-risk individuals. Through the candidate’s didactic coursework and mentorship plan, Dr. Murff will develop additional skills in genetics, cancer biology, and molecular epidemiology. The latter phases of the award will build on this new knowledge to investigate the genetic underpinnings of familial colon cancer. The experience gained from this career development award will ensure Dr. Murff’s transition into an independent researcher in cancer epidemiology. Funded by the National Cancer Institute Investigators: Harvey Murff, M.D., M.P.H. (PI)
Nashville Breast Health Study
This proposal is for a population-based case-control study of breast cancer in Nashville, Tennessee. The primary hypotheses are 1) regular use of nonsteroidal anti-inflammatory drugs (NSAID) may reduce the risk of breast cancer, and this association may be modified by the genotypes of NSAID metabolizing enzymes; 2) well-done (charred) meat intake, and thus exposures to the mammary carcinogens heterocyclic amines and polycyclic aromatic hydrocarbons, may be related to an increased risk of breast cancer, particularly among women with certain genotypes of the carcinogen-metabolizing enzymes; 3) the positive association between well-done meat intake and breast cancer risk may be modified by regular NSAID use; 4) certain polymorphic genes involved in estrogen metabolism may interact with each other in the etiology of breast cancer. We propose to recruit 1,500 incident cases and 1,500 controls for this case-control study. Breast cancer cases will be identified through a rapid case-ascertainment system established for the study. Controls will be selected randomly from the general population and frequency-matched to cases by age and race. Telephone interviews will be conducted to obtain relevant exposure information. Exfoliated buccal cell samples will be collected to extract DNA for analyzing 38 polymorphisms in 14 candidate genes that are involved in the metabolism of NSAIDs, mammary carcinogens, and estrogens. DNA samples will also be stored for future studies of additional genetic factors and their interactions with lifestyle factors in the risk of breast cancer. NSAIDs are among the most commonly used medications, and high-temperature cooking has been widely used for meat preparation. Information regarding their associations with breast cancer risk could have important public health implications in the primary prevention of breast cancer. Studies investigating gene-gene and gene-environment interaction could provide valuable information in identifying high-risk individuals for designing cost-effective preventive strategies for breast cancer. Funded by the National Cancer InstituteInvestigators: Wei Zheng, M.D., Ph.D. (PI); Mark C. Kelley, M.D.; Sandy Deming, Ph.D.; Xiao Ou Shu, M.D., Ph.D.; Martha J. Shrubsole, Ph.D.; Qiuyin Cai, M.D., Ph.D.; Jirong Long, Ph.D.; Fritz F. Parl, M.D., Ph.D.; Bill Dupont, Ph.D.; David Page, M.D.
Nashville Men’s Health Study: Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer
Prostate cells respond to estrogens, insulin, and other factors largely regulated in men by adipose mass. Several recent studies report obesity associated with high-grade prostate cancer, progression, and mortality, however the association with low-grade cancer common in the PSA era remains unclear. Challenges include measuring fat deposition patterns, excluding latent cancer from control groups, and controlling for several potential biases associated the effects of obesity on prostate cancer detection. Our study aims to address these challenges and determine the relationship between total adiposity (e.g., BMI, estrogens) and visceral adiposity (e.g., waist circumference, waist-to-hip ratio (WHR), insulin) across high-grade cancer, low-grade cancer, and prostatic intraepithelial neoplasia (PIN). Preliminary analyses (R21 CA98348, n=304 cancer, 120 PIN, 424 controls) found WHR significantly associated with PIN (WHR>1.03: OR = 4.75 95% Cl (1.71, 13.2), ptrend<0.01, adjusted for PSA, BMI, prostate volume, age race, ORE result, # cores). Also, BMI>35 was associated with high-grade (Gleason score=7) cancer (ORadj=3.49 (0.84, 14.4), ptrend = 0.05). Thus, visceral adiposity and the related metabolic syndrome may impact early prostate carcinogenesis, while an estrogen- rich environment associated with greater BMI may accelerate progression to high-grade/clinically relevant disease. Using our established multi-centered rapid-recruitment protocol, we will recruit an additional 1,106 prostate cancer cases (42% Gleason score=7), 435 PIN cases, and 1,544 controls without cancer or PIN at prostate biopsy. Data and specimens (questionnaires for diet, physical activity, and other risk factors; body measures for BMI, WHR, sitting height, and percent body fat (BIA); blood for DNA and hormone levels) are collected before diagnosis. Genes representing pathways linking total adiposity (e.g., Lep, LepR, CYP19, ER,AR, SHBG) or visceral adiposity (Res, Adip, AdipR1/2, INS, IRS1/2, IGF1, IGFBP3, PPARy2) to PIN or cancer will be investigated using multivariable logistic regression. Also, we will investigate blood markers of adiposity and PIN in an individually matched analysis (total adiposity: leptin, E2/T ratio, SHBG; visceral adiposity: HbA1c, adiponectin, resistin). Obesity is epidemic in the U.S., and prostate cancer is a leading cause of cancer-related death. Ongoing chemoprevention studies target PIN, and our results may identify new obesity-based prevention approaches or improve the prognosis of prostate cancer patients. Funded by the National Cancer Institute Investigators: Jay H. Fowke, M.P.H., Ph.D. (PI); Joseph Smith, M.D.; Saundra Motley, R.N. ; Raoul Concepcion, M.D.
Southern Community Cohort Study (SCCS)
It has long been known that cancer incidence and mortality are elevated among African Americans. The Southern Community Cohort Study (SCCS) is a landmark prospective investigation into the determinants of these disparities. Over the past five years, by partnering with Community Health Centers (CHCs), facilities providing basic health care mainly to the uninsured across 12 southern states, we have overcome barriers that have traditionally restricted participation of African Americans in health studies. The current phase of the SCCS, proposed herein, will enable completion of enrollment so that the cohort will include approximately 90,000 men and women, nearly 70% African American, age 40-79. The new enrollees will be recruited from CHCs and complete an in-person interview about medical, lifestyle and other characteristics, with > 90% expected to provide biologic specimens (blood, buccal cells, and/or urine). Follow up of the entire cohort to identify deaths and incident cancers and update exposure profiles will be carried out. We will implement enhanced approaches to active follow up. Longitudinal analyses and nested case-cohort studies using the interview data and biologic specimens will be initiated during this funding period to evaluate specific hypotheses about cancer among African Americans which can uniquely or with special advantage be assessed within the SCCS. The hypotheses are related to energy balance (weight gain, obesity and physical inactivity), vitamin D, inflammation, selenium and other nutrient intakes, tobacco metabolism, and cancer screening practices and their impact on incidence and/or mortality of the major cancers (lung, prostate, breast, and colon/rectum). Initial SCCS data show sometimes marked racial differences in these variables. The cohort possesses attributes, such as a 44% prevalence of obesity (reaching 57% among Black women) and a 44% prevalence of current smoking which place it at exceptionally high risk of cancer. The SCCS is thus unique among all cohorts and comprises a population of urban and rural blacks and whites, often of low income, seldom if ever included in previous studies. The SCCS is a national resource, with comprehensive biologic and questionnaire data available for assessing, both within the SCCS and in combination with other molecular epidemiology consortia, the etiology of cancer and reasons for the largely unexplained higher rates among blacks. The ultimate public health benefit will be progress towards the development of measures aimed at cancer prevention, the elimination of cancer inequalities, and reduction of the cancer burden among all groups. Funded by the National Cancer Institute Investigators: William Blot, Ph.D. (PI); Lisa Signorello, Ph.D. (PI); Maciej Buchowski, Ph.D.; Raymond Burk, M.D.; Qiuyin Cai, M.D., Ph.D.; Robert Dittus, M.D., M.P.H.; Jay H. Fowke, M.P.H., Ph.D.; Jirong Long, Ph.D.; Chun Li, Ph.D.; Charles E. Matthews, Ph.D.; Pierre Massion, M.D.; Joseph McLaughlin, Ph.D.; Neeraja Peterson, M.D.; David Schlundt, Ph.D.; Martha Shrubsole, Ph.D.; Xiao Ou Shu, M.D., Ph.D.; Robert Tarone, Ph.D.; Scott Williams, Ph.D.; Wei Zheng, M.D., Ph.D.