Recent Research in Genetic & Molecular Epidemiology
Adipose Related Biomarkers of Prostate Cancer
Association Studies of Regional Genome Scan to Identify Breast Cancer Susceptibility Genes
Biomarkers of Methionine Metabolism and Risk for Colorectal Adenoma
Breast Cancer Survival: Lifestyle & Genetic Determinants
Cell Cycle/Apoptosis Gene Variants and Breast Cancer Risk
Diet, Genetics, Epigenetics and Colorectal Adenoma Risk
Dietary Calcium and Magnesium, Genetics, and Colorectal Adenoma
Energy Homeostasis and Cancer: Biomarkers and Lifestyles
Epidemiologic Study of Predictors for Adenoma Recurrence
Genetic Consequences of Therapies for Cancer
Genetic Epidemiology of Multiple Sclerosis
Genetic Factors for Breast Cancer – A Genome Wide Study
Genetic Studies of Dementia in the Amish
Inflammatory Biomarkers and Colorectal Cancer Risk
Iron as a Nutritional Modifier of Antiretroviral Treatment Complications in HIV/AIDS
Lung Cancer Risk and Inflammatory Pathways
Magnesium, Calcium and Risk for Colorectal Adenoma
Mechanisms and Management of Familial Colorectal Cancer
Molecular Epidemiologic Study of Breast Cancer
Nashville Men’s Health Study: Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer
National Children’s Study
Shanghai Breast Cancer Study (renewal)
Shanghai Breast Cancer Study
Shanghai Endometrial Cancer Study (SECS)
Southern Community Cohort Study (SCCS)
Tumor Markers and Recurrent Adenomas: A Follow-up Study
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)
Association Studies of Regional Genome Scan to Identify Breast Cancer Susceptibility Genes
This is an ongoing study to perform regional fine mapping to identify candidate genes for breast cancer in two chromosome regions. In this DOD-funded IDEA award, we will use a multiple-phase study design to gain study efficiency, reduce costs, and balance both type I and type II errors. We will 1) perform regional fine mapping to identify candidate genes for breast cancer in two chromosome regions; 2) identify all common sequence variants in the functional regions of identified candidate genes; 3) evaluate the association of sequence variants with breast cancer risk in the Shanghai Breast Cancer Study (SBCS); and 4) confirm the associations in the Nashville Breast Health Study (NBHS). Gene-gene and gene-environment interactions will also be evaluated. Funded by the Department of Defense (DOD), Congressionally Directed Medical Research Programs Investigators: Qiuyin Cai, M.D., Ph.D. (PI); Xiao-Ou Shu, M.D., Ph.D.; Wei Zheng, M.D., Ph.D.; Chun Li, Ph.D.; Jirong Long, Ph.D.; Chuanzhong Ye, M.D., Ph.D.
Biomarkers of Methionine Metabolism and Risk for Colorectal Adenoma
Colorectal cancer is one of the most common malignancies and is the second leading cause of cancer death in the United States. Most of these cancers arise from adenomatous polyps. Factors involved in one-carbon metabolism and aberrations in methylation reactions have been implicated in previous studies of colorectal neoplasia. Methionine metabolism is a key component in one-carbon metabolism and it is integrally involved in most physiologic methylation reactions including DNA and RNA methylation. S-adenosylhomocysteine (SAH), the precursor to homocysteine, has been proposed as a more sensitive marker of alterations in methionine metabolism than homocysteine. Additionally, the ratio of s-adenosylmethionine (SAM) to SAH is a marker of methylating capacity and a lower SAM:SAH is related to increased DNA hypomethylation. However, neither of these markers has been evaluated in relation to cancer risk. We hypothesize that a high SAH level and a low SAM:SAH ratio are associated with an increased risk of colorectal adenoma. In this proposed study, we will evaluate these hypotheses by conducting a nested case-control study using plasma samples collected as part of the Tennessee Colorectal Polyp Study (TCPS; P50CA95103), an on-going colonoscopy-based case-control study of colorectal adenoma. We will measure SAH and SAM levels in 265 cases and 265 matched controls. The hypotheses proposed in the application are novel and based on strong biological plausibility. Results from this study will not only be useful to understand one-carbon metabolism and colorectal neoplasia but also be informative for developing a sensitive biomarker for identifying high-risk individuals for cost-effective colorectal screening and chemoprevention. Funded by the National Cancer Institute Investigators: Martha Shrubsole, Ph.D. (PI); Wei Zheng, M.D., Ph.D.
Breast Cancer Survival: Lifestyle & Genetic Determinants
The population of women who survive breast cancer is rising rapidly. Despite the success of initial treatments, many patients constantly battle fears of disease recurrence and early death. However, the effect of non-clinical factors, particularly genetic factors, on breast cancer outcomes is largely unknown. The proposed study will use the existing resources of two well-established cohort studies of 3593 breast cancer patients to comprehensively evaluate the following hypotheses: 1) Breast cancer survival may be associated with genetic polymorphisms in genes encoding angiogenic factors and matrix metalloproteinases, both of which are essential for tumor growth and metastasis. 2) Infiltrating inflammatory cells, particularly tumor- associated macrophages, can produce a large variety of promalignant cytokines and growth factors. Genetic polymorphisms in inflammatory chemokine and cytokine genes may be related to breast cancer survival. 3) Transforming growth factor-B promotes the growth and progression of breast cancer, and genetic polymorphisms in TGF-R pathway genes may be related to breast cancer survival. 4) The cyclooxygenase-2 (COX2) gene is up-regulated in a large proportion of mammary tumors, and this enzyme initiates the biosynthesis of various prostaglandins with diverse, and sometimes opposing, effects on tumorigenesis. Genetic polymorphisms of prostaglandin-pathway genes may be associated with breast cancer survival. A two-phase study design will be applied. In Phase I, all functional variants plus haplotype-tagging single nucleotide polymorphisms (SNP) will be genotyped among 1193 breast cancer patients who have been followed for an average of 7.1 years. All promising associations identified in Phase I will be evaluated in Phase II in an on-going cohort study of 2400 cancer patients (being followed for 5 years). The large sample size and two-phase study design will balance both Type I and Type II errors and provide credible results towards improving the understanding of associations between genetic factors and breast cancer outcomes. Identifying factors that predict risk of relapse and rates of mortality will not only affect the expanding cancer survivor population by providing evidence-based information, but will also positively influence the medical care system and economy at large by making treatment more effective and cost-efficient. The proposed study, built on successfully implemented cohort studies, will be extremely timely and cost-efficient. Funded by the National Cancer Institute Investigators: Xiao Ou Shu, M.D., Ph.D. (PI)
Cell Cycle/Apoptosis Gene Variants and Breast Cancer Risk
It is well established that genetic factors play a major role in breast tumorigenesis. However, the known breast cancer susceptibility genes account for only a minority of breast cancer cases in the general population. Cumulative evidence from in vitro and animal studies suggests that the genes involved in the cell-cycle control and apoptosis pathways may be related to breast cancer. The cell-cycle control and apoptosis pathways function as an integrated molecular network, and perturbations in one pathway can have profound consequences on the other. In this study, we will investigate genetic variations of major genes involved in the cell-cycle control and apoptosis pathways in relation to breast cancer risk. The proposed study will use data and biological samples collected from the Shanghai Breast Cancer Study (SBCS, R01CA64277). Genetic polymorphisms in 25 candidate genes in the cell-cycle control and apoptosis pathways will initially be evaluated using both the genotype- and haplotype- approaches in 1,250 cases and 1,250 controls recruited from 1996 to 1998. Promising associations identified in the initial phase will be re-evaluated in a second set of subjects (1,850 cases and 1,850 controls) recruited from 2002 to 2005. This two-phase study design will effectively balance both Type I and Type 2 statistical errors and provide credible results towards our understanding of the etiology of breast cancer. We will use the multifactor-dimensionality reduction (MDR) statistical method to investigate any gene-gene interaction in relation to breast cancer risk. We will 1) investigate interaction between genetic polymorphisms with endogenous estrogen exposure related factors in relation to breast cancer risk; 2) evaluate whether genetic polymorphisms may be associated with the risk of specific subtypes of breast cancer; and 3) conduct in vitro experiments to evaluate the function of genetic variations to further confirm the biological relevance of the association. With its large size and strong methodology, the SBCS provides a great opportunity to investigate gene-gene and gene-environment interactions in relation to breast cancer risk. The findings from the study are likely to significantly advance our knowledge of the etiology of breast cancer and will be valuable for identifying high risk women for the primary and secondary prevention of breast cancer. Funded by the National Cancer Institute Investigators: Qiuyin Cai, M.D., Ph.D. (PI); Wei Zheng, M.D., Ph.D.; Xiao-Ou Shu, M.D., Ph.D.; Jirong Long, Ph.D.; Wanqing Wen, M.D.; Marylyn Ritchie, Ph.D.; Yinghao Su, M.D., Ph.D.; Shimian Qu, Ph.D. Diet, Genetics, Epigenetics and Colorectal Adenoma Risk This research examines lifestyle, genetic and epigenetic susceptibility, and colorectal adenoma risk. Folate, a B vitamin, is essential for regenerating methionine, the methyl donor for DMA methylation. Evidence of a role of low folate and/or methionine in colorectal adenoma/cancer risk is accumulating. Simultaneously, there is increasing evidence that aberrant DNA methylation, such as hypermethylation of tumor suppressor genes, is increased in both colorectal cancers and adenomas. To advance our understanding of the role of diet and DNA methylation in adenoma development, epidemiologic studies examining the role of these factors and genes involved in DNA methylation associated pathways are needed. Thus, the research goals of this proposal are to evaluate in a large colorectal adenoma case-control study (n=3000) risk associated with methyl-group intake (folate, methionine, vitamin B6, vitamin B12), polymorphisms in genes involved in methyl-group transfer (MTHFR, DNMT1, DNMT3A), promoter methylation of tumor suppressor genes in normal rectal mucosa (APC, RASSF1 A, n=4DO), and the combined association of these factors. The methylation phenotype in normal rectal mucosa will be compared with methylation phenotype in adenomas. Additionally, the potential utility of methylation phenotype in normal rectal mucosa as a marker of adenoma risk will be evaluated by studying factors that affect level of methylation. This work will extend our understanding of links between DNA methylation and adenoma risk as well as interactions with genetic susceptibility. It may also serve to help identify high-risk populations for colorectal adenoma. Funded by the National Cancer Institute Investigators: Martha Shrubsole, Ph.D. (PI); Wei Zheng, M.D., Ph.D.; Robert Coffey, M.D.; Wael El-Rifai, M.D., M.Sc., Ph.D.; Jonathan Haines, Ph.D.; Jirong Long, Ph.D. Dietary Calcium and Magnesium, Genetics, and Colorectal Adenoma Results have been inconsistent on the protective effect of calcium and magensium intake on colorectal cancer and adenoma. We found recently in the Tennessee Colorectal Polyp Study (TCPS; P50CA95103) that the associations between intake of calcium or magnesium and risk of colorectal adenoma and hyperplastic polyps may differ by the common Thr1482Ile polymorphism of the TRPM7 gene, a gene involved in calcium and magnesium (re)absorption and homeostasis. Our finding may partially explain the inconsistency in previous studies on calcium and magnesium. In addition, we found that the ratio of calcium to magnesium intake significantly interacted with the Thr1482Ile polymorphism in relation to both adenomatous and hyperplastic polyps. In response to PAR-07-377, we propose a clinical epidemiologic study to test several novel hypotheses regarding gene-nutrition interactions using data and biological samples collected as part of the TCPS, a large on-going molecular epidemiologic case-control study of colorectal adenoma. Specifically, we will 1) confirm our pilot finding in an independent set; and 2) conduct a two-phase study to evaluate the relationships between other polymorphisms in 14 candidate genes involved in magnesium and calcium (re)absorption, regulation and balance and risk of colorectal adenoma; and investigate whether the associations between intake of calcium and magnesium or the ratio of calcium to magnesium intake and risk of colorectal adenoma differs by the genotypes or haplotypes in the 14 genes. The first phase of the study will include 1200 cases and 2400 controls to comprehensively investigate promising polymorphisms and their interactions with nutrients. All promising variants will be re-evaluated in an independent set of 800 cases and 1600 controls to validate the identified associations or nutrient-gene interactions. The proposed two-phase study design will allow us to effectively address potential false positive findings (Type I error), one of the most serious concerns regarding association studies of low-penetrance genetic factors and will allow us to enhance the statistical power for evaluation of gene-gene and gene-nutrition interactions. The results from our study will help to identify people at a high risk of colorectal adenoma and to develop personalized strategies of dietary changes or nutritional fortification to prevent occurrence of colorectal adenoma, and, thus, colorectal cancer. In the general U.S. population, 1 in 18 individuals will develop colorectal cancer over their lifetime and forty percent will die within five years of diagnosis, mainly due to diagnosis at a late stage. Therefore, development of primary preventive strategies for colorectal cancer is critical. The results from our study will help to identify people at a high risk of colorectal adenoma and to develop personalized strategies to prevent occurrence of colorectal adenoma, and, thus, colorectal cancer through dietary changes or nutritional fortification. Funded by the National Center for Complementary and Alternative Medicine Investigators: Qi Dai, M.D., Ph.D.; Jirong Long, Ph.D.; Reid M. Ness, M.D.; Marylyn Ritchie, Ph.D.; Jiajun Shi, Ph.D.; Martha J. Shrubsole, Ph.D.; Wei Zheng, M.D., Ph.D. Energy Homeostasis and Cancer: Biomarkers and Lifestyles Recognition that adipose tissue is both an energy reservoir and a source of proteins with endocrine functions (adipokines), suggests that these proteins, and the genes controlling them, are part of the homeostatic control mechanisms that regulate cell growth. To advance our understanding of the role of energy homeostasis and cancer, epidemiologic studies examining the role of genes involved in energy regulation in humans, as well as the interactions of these exposures with lifestyle factors associated with energy balance are needed. Accordingly, the four aims of this research are as follows. In a case-control study of breast cancer (N=2,500), Aim 1 will examine the effect of polymorphisms in genes involved in energy homeostasis (insulin, IGF-1, leptin, and adiponectin), and Aim 2 will examine gene-environment interactions between these genes and lifestyle factors associated with energy balance (physical activity, energy intake, body size). In a case-control study of adenomatous polyps (N=1,400), Aim 3 will examine the effect of lifestyle factors associated with energy balance (as above), and (Aim 4) will examine the effect of polymorphisms in genes involved in energy homeostasis (as above). Primary research support will come from existing molecular epidemiology studies of the candidate’s mentor. Resources from this award will support genotyping of adipokines not originally examined in these studies. This work will extend our understanding of links between energy homeostasis and cancer, as well as interactions between genetic susceptibility, lifestyle factors, and cancer. This work will also serve as the basis for submission of competitive R01 proposals by the candidate in latter years of this award. Funded by the National Cancer Institute Investigators: Charles E. Matthews, Ph.D. (PI) Epidemiologic Study of Predictors for Adenoma Recurrence Most colorectal cancers arise from adenomatous polyps, and a large proportion of adenoma patients will develop new adenomas after their initial polypectomy. There is considerable controversy regarding an appropriate surveillance interval for adenoma patients following the removal of their initial adenomas. Therefore, studies assessing predictors for recurrent adenoma, particularly among patients with multiple or pathologically advanced adenoma(s), will provide valuable information for designing individualized, cost-effective surveillance and chemoprevention strategies for adenoma patients. Some tumor markers (genetic or epigenetic alternations) involved in the formation of colorectal neoplasms are promising predictors for recurrent adenomas, as they are believed to reflect a field cancerization process or a genetic predisposition to colon adenomas. We hypothesize that patients whose initial adenomas have certain altered genetic or epigenetic profiles may have an elevated risk of adenoma recurrence, and these tumor markers, along with pathologic features of initial adenomas can be used to predict the risk of adenoma recurrence. To evaluate these hypotheses we propose in this application a series of investigations, consisting of both hypothesis-testing and hypothesis-generating components as described below. For the reasons described in section BI, the major focus of this application will be on the study of predictors for recurrent adenomas among patients with multiple or pathologically advanced adenoma(s). Funded by the National Cancer Institute Investigators: Wei Zheng, M.D., Ph.D. (PI) Genetic Consequences of Therapies for Cancer Over 270,000 survivors of childhood cancer are estimated to be alive today in the United States alone; many are able to have children of their own. Consequently, possible effects of curative cancer treatments (like radiation and chemotherapy) on inherited disorders are increasingly important. However, there is little understanding of genetic consequences of treatment or whether underlying susceptibility can be transmitted to offspring. Further, young adults diagnosed with cancer at ages 20 to 34 years are often overlooked in studies of late effects. While there is little evidence that mutagenic therapies result in transgenerational effects, few studies have looked at risk in terms of treatment dose to testes or ovaries. In this research all persons diagnosed with cancer under age 35 after 1943 in Denmark and after 1952 in Finland are being identified, along with their siblings. Among the 10,000 children with cancer who survived to reproductive ages, 3,000 are estimated to be the parents of 5,600 children. Among the 38,000 patients diagnosed with cancer as young adults, 25,000 survived and had 14,000 children after their cancer diagnosis. Thus, 19,600 offspring of cancer survivors can be studied. Rosters of siblings and their offspring are being developed for comparison purposes. The offspring cohorts in Denmark and Finland will then be linked to outcome registries to identify cancer, birth defects, stillbirths and neonatal and other deaths. Medical records of the cancer survivors will be obtained and radiation records and chemotherapy information abstracted. Radiation doses to gonads (and uterus for females) will be calculated, and the genetic consequences of curative therapies will be assessed. Gonadal exposures to radiation or chemotherapy for many cancer survivors will be high – just below the threshold for infertility. Blood will be collected from a sample of survivors, their spouses, and their offspring to examine mechanistic processes related to cancer predisposition and effect of therapy on health outcomes. Two hundred families will donate lymphocytes and DNA for storage and analyses to include the G2 radiation assay to assess chromosomal radiosensitivity (that might be related to alterations of DNA damage-response/repair genes); to determine whether such a sensitivity can be inherited; to evaluate specific repair genes (e.g. XRCC1) for variant polymorphisms; and to investigate minisatellite inheritance. The study will help answer questions about genetic consequences of mutagenic exposures, explore whether susceptibility states and specific genetic polymorphisms conferring susceptibility can be identified for specific cancers, and evaluate the extent to which-identified susceptibility or genetic damage can be transmitted to future generations. Funded by the National Cancer Institute Investigators: John Dunning Boice, Sc.D. (PI) Genetic Epidemiology of Multiple Sclerosis Multiple Sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder affecting more than 400,000 individuals in the United States. Myelin loss, gliosis, and varying degrees of axonal pathology culminate in progressive neurological dysfunction including sensory loss, weakness, visual loss, vertigo, incoordination, sphincter disturbances, and altered cognition. The evidence for a genetic influence in MS is overwhelming; however the etiology springs not from a single major gene, but from multiple genes acting either independently or interactively. This complexity has made the search for the responsible genetic variations difficult. A candidate gene approach identified allelic association with the HLA-DR2 allele but no other allelic associations have been confirmed. In the current funding cycle we completed a second-generation genomic screen and initial follow-up has identified one strong chromosomal linkage signal congruent with other studies. We also generated exciting data suggesting that the expression of clinical symptoms of MS is influenced by genomic variation(s) in or near APOE on chromosome 19q13. With the explosion of data from the human genome project, new methods of laboratory and statistical genetic analysis, and substantial expansion of our MS dataset, we can now take new approaches toward dissecting the complex genetics of MS. To achieve these goals, we propose five specific aims (1): To examine in detail chromosome 1q42 to identify the underlying MS risk zone; (2): To analyze SNPs in and near APOE for allelic associations to MS disease expression; (3): To test for association between MS and genes involved in oxidative stress; (4): To examine genes identified through expression analysis in MS tissues and acting in critical pathways; and (5): To test for gene-gene interactions. All analyses will take into account the known association with the HLA-DR2 allele seen in both our Caucasian and African-American datasets. We will genotype over 200 multiplex families, 1,500 Caucasian US singleton families, 1,000 Caucasian UK singleton families, 1,000 controls, and 1,000 African-American singleton families. Funded by the National Institute on Aging Investigator: Jonathan L. Haines, Ph.D. (PI) Genetic Factors for Breast Cancer – A Genome Wide Study Breast cancer is the most common malignancy among women in many parts of the world. Genetic factors play an important role in the etiology of breast cancer. However, to date, only a few breast cancer susceptibility genes have been identified, and they explain only a very small fraction of breast cancer cases in the general population. A large number of candidate-gene studies have been conducted over the past 10 years. These studies, however, are clearly inadequate to fully uncover the genetic basis of breast cancer. With recent significant advances in high-throughput genotyping technologies, it has become feasible to conduct genome-wide association (GWA) studies to systematically evaluate genetic risk factors for breast cancer. The multi-phase GWA study proposed in this application will be built upon the resources established in two large, on-going studies funded by NCI, the Shanghai Breast Cancer Study (R01 CA64277) a population-based case-control study, and the Shanghai Women´s Health Study (R01 CA70867) a population-based prospective cohort study. Approximately 8,000 breast cancer cases and controls will be included in this proposed study. In the first phase of the study, we will conduct a GWA scan in 1,000 cases and 1,000 controls using the Illumina HumanHap550 Beadchip. We will then select the 10,600 most promising SNPs for a validation study in an independent sample of 1,500 cases and 1,500 controls. All promising SNPS will be further validated using data from 1,000 cases and 2,000 controls selected from the prospective Shanghai Women´s Health Study. The parent projects of this newly-proposed study have been exceptionally well-conducted with a strong methodology. The feasibility and utility of the proposed study have been clearly demonstrated in our pilot study. The study is unique and has many unique features that facilitate a rigorous evaluation of breast cancer genetic factors. The results from this study will be valuable in identifying high risk women for primary and secondary prevention of breast cancer. Funded by the National Cancer Institute Investigators: Wei Zheng, M.D., Ph.D. (PI); Jirong Long, Ph.D.; Chun Li, Ph.D.; Qiuyin Cai, Ph.D., M.D.; Xiao Ou Shu, M.D., Ph.D.; Jonathan L. Haines, Ph.D. Genetic Studies of Dementia in the Amish Alzheimer disease (AD) is the most common form of dementia in the elderly. Overwhelming evidence demonstrates that the etiology of AD is a complex web of genetic and environmental factors. Early success in genetic studies has confirmed that AD risk is associated with four genes (APR, PS1, PS2, APOE), with by far the greatest proportion explained by the APOE-4 allele. However, together these genes account for less than half of the total genetic risk in AD. In contrast to this early success, finding the additional genes has been very difficult. Many studies in general outbred populations have identified numerous genomic regions of interest through linkage analysis and numerous candidate genes through association analysis. However, none of these regions or genes has yet yielded a new, confirmed, AD susceptibility gene. An alternative, complementary, and powerful approach for finding these genes is to use genetically isolated founder populations where large interrelated pedigrees can be ascertained, the environmental exposures are less variable, and the underlying genetic etiology for dementia is more homogeneous. The Amish communities of central Ohio and northern Indiana are ideal for this purpose. Over the past five years we have greatly extended our ascertainment in these communities, having already enrolled nearly 1,300 individuals and collected a wealth of clinical data. We have started genetic characterization of the Amish pedigrees through pedigree analysis, a preliminary microsatellite genome-scan, and tests of several candidate genes. Two chromosomal regions and two candidate genes have already generated interesting results. We have more than doubled the initial dataset and with advances in genomic technologies, we can take full advantage of the Amish family resource by integrating our clinical and family data with a high-density single nucleotide polymorphism (SNP) panel to localize AD genes. This approach will help us accomplish our goal of identifying at least one AD gene. Our specific aims are to: 1). Continue ascertainment in the Amish communities; 2). Perform a whole-genome SNP scan; 3). Localize AD genes using the SNP scan data; 4). Refine these minimum candidate regions and identify high priority candidate genes; and 5). Exhaustively examine these genes for association to AD in both the Amish and outbred datasets. Funded by the Agency for Health Care Research and Quality Investigator: Jonathan L. Haines, Ph.D. (PI) Inflammatory Biomarkers and Colorectal Cancer Risk Colorectal cancer (CRC) is a major cause of cancer deaths in the United States and many other countries. Chronic inflammation has been suggested to play a major role in the pathogenesis of CRC. We propose in this application to conduct a nested case-control study within the Shanghai Women’s Health Study, a large population-based prospective cohort study, to evaluate the association of CRC risk with measures of several key products of the inflammatory process and with related genetic markers of inflammation. Specifically, we will include 580 incident cases of CRC and their individually matched controls (1 to1 match for biochemical markers and 1 to 3 match for genetic markers). Urine samples collected at baseline will be measured for a major metabolite of prostaglandin E2 (PGE2) using a liquid chromatographic/mass spectrometric assay and F2-isoprostanes using the mass spectrometric method. Baseline blood samples will be measured for soluble tumor necrosis factor-a receptors, interleukin-6, and C-reactive protein. Genomic DNA will be assayed for polymorphisms in genes involved in PGE2 production (PTGS2, PTGES), metabolism (15-PGDH), and signaling (PTGER1-PTGER4). We will perform statistical analyses to evaluate the associations between these biochemical and genetic markers of inflammation and CRC risk and potential interactions of these markers. Given the large sample size, the prospective study design, the availability of comprehensive baseline survey data and biospecimens, as well as the excellent collaborative environment, we believe that this proposed study represents a unique opportunity to evaluate, vigorously and cost-efficiently, the relationship between various markers of inflammation and CRC. Overall, this study will contribute significantly to the understanding of the role of inflammation in the etiology of CRC and to the development of new strategies for the assessment of CRC risk. Funded by the National Cancer Institute Investigators: Gong Yang, M.D., M.P.H. (PI); Wei Zheng, M.D., Ph.D.; Xiao Ou Shu, M.D., Ph.D.; Jason Morrow, M.D.; Ginger Milne, Ph.D.; Qiuyin Cai, M.D., Ph.D.; Xianglan Zhang, M.D., M.P.H.; Wanqin Wen, M.D.; Jirong Long, Ph.D.; Leena Choi, Ph.D. Iron as a Nutritional Modifier of Antiretroviral Treatment Complications in HIV/AIDS Access to highly active anti-retroviral drug therapy has markedly reduced morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). Although the incidence of most of the neurological complications of HIV infection has declined dramatically with the use of these drug regimens, peripheral neuropathy (PN), a devastating complication of nucleoside reverse transcriptase inhibitor (NRTI) therapy, is increasingly common among persons living with HIV/AIDS. The precise mechanisms of nerve damage in PN are unclear, but important factors include: nerve inflammation caused by HIV-infected macrophages, drug-induced mitochondrial abnormalities leading to oxidative stress, and poor nutrition. Iron metabolism is abnormal in HIV infection, but the role of iron, a micronutrient critical for mitochondrial and neuronal function, has not been directly explored in HIV-associated PN. A common variant in the hemochromatosis (HFE) gene, C282Y, causes increased dietary iron absorption and defects in cellular iron transport and immunity. Expression of the HFE-encoded iron-transport protein on macrophages has been shown to decrease as result of HIV-1 infection. We previously used clinical data and stored DNA from a large, prospective cohort study conducted by the AIDS Clinical Trials Group (ACTG) to make the seminal observation that HFE C282Y may protect against the development of PN and other inflammatory complications of NRTI therapy in HIV/AIDS. Since this iron-loading variant is protective against PN, and iron deficiency is endemic in many populations devastated by HIV/AIDS, it is critical to define the mechanism underlying this protective effect in order to benefit patients globally. The goals of this study are therefore to use cryopreserved serum samples in the same HIV cohort to determine 1) if reduced PN in HFE C282Y carriers is due to increased body iron stores, 2) if time to onset of PN during NRTI therapy is related to systemic iron stores before starting treatment, 3) if a statistical model incorporating iron stores, early changes in iron levels during NRTI therapy; HFE genotype, and high-risk mitochondrial DNA variants can be developed to predict the development of PN. Conventional regression as well as newer statistical modeling tools will be used. These studies will generate critical preliminary data for an R01 grant application to fund in-depth mechanistic studies that we hope will ultimately enable clinicians to reduce the incidence of this debilitating complication of HIV/AIDS treatment. Funded by the National Heart Lung and Blood Institute Investigators: Asha Kallianpur, M.D., M.P.H.(PI); David Haas, M.D.; Todd Hulgan, M.D., M.P.H.; Wanqing Wen, M.D.; Jeffrey Canter, M.D., M.P.H.; Marylyn Ritchie, Ph.D. Lung Cancer Risk and Inflammatory Pathways This is a major project (project 5) of the Vanderbilt Lung Specialized Program of Research Excellence (SPORE). In this study, we will conduct a large nested case-control study within two NCI-funded cohort studies, the Shanghai Women’s Health Study (SWHS) and the Southern Community Cohort Study (SCCS), to investigate biomarkers of inflammation in relation to subsequent lung cancer risk. We will include an estimated 1,130 incident cases of lung cancer that are newly diagnosed after the baseline survey, and an equal number of individually matched controls. Functional/suspected functional polymorphisms and haplotypes in genes involved in PGE2/PGI2 formation and metabolism will be determined for all the cases and controls. For those with urine and/or blood specimens collected at baseline, we will measure urinary levels of PGE-M, PGI-M, and LTE4, as well as blood levels of C-reactive protein (CRP). Odds ratios (ORs) adjusted for smoking and other variables will be calculated to measure and test the significance of associations between these biochemical and genetic markers of inflammation and lung cancer risk. Funded by the National Cancer Institute Investigators: Qiuyin Cai, M.D., Ph.D. (PI); William Blot, Ph.D.; Wei Zheng, M.D., Ph.D.; Xiao-Ou Shu, M.D., Ph.D.; Jirong Long, Ph.D.; Wanqing Wen, M.D.; Lisa Signorello, Ph.D. Magnesium, Calcium and Risk for Colorectal Adenoma High intake of calcium may protect against both colorectal cancer and adenoma, however, results have been inconsistent. Magnesium, the second most abundant intracelluar cation in the body, plays an essential role in over 300 biological activities. Ionized magnesium counters the action of ionized calcium in many physiologic activities. The ratio of calcium to magnesium intake is much higher in the US than in East Asian populations with traditionally low risks of colorectal cancer and other chronic diseases. However, accurate measurement of body magnesium status has always been difficult in previous epidemiologic studies. We found very recently in the Tennessee Colorectal Polyp Study (TCPS), a large on-going molecular epidemiologic case-control study of colorectal adenoma, that dietary intake of magnesium may reduce the risk of adenoma, a cancer precursor, particularly when the calcium/magnesium intake ratio is low, whereas under the same conditions, intake of calcium may be associated with a decreased risk. Based on these promising pilot data, we propose a molecular epidemiologic study to confirm our new findings and test some new hypotheses using data and biological samples collected in TCPS. Primarily, we will evaluate whether erythrocyte magnesium in relation to adenoma risk. The results from our study will help to identify people at a high risk of colorectal adenoma and to develop personalized strategies to prevent occurrence of colorectal adenoma, and, thus, colorectal cancer through dietary changes or nutritional fortification. Funded by the American Institute for Cancer Research Investigators: Qi Dai, M.D., Ph.D. (PI); Jirong Long, Ph.D.; Reid M. Ness, M.D.; Martha J. Shrubsole, Ph.D. ; Wei Zheng, M.D., Ph.D. 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) Molecular Epidemiologic Study of Breast Cancer Most epidemiological studies of breast cancer have focused on investigations of genetic polymorphisms in the genes involved in estrogen and carcinogen metabolism. A number of promising associations have been identified, many of which have yet to be replicated. In this competitive renewal application, we propose to confirm some of the promising associations identified in the initial funding cycle and extend our work to the investigation of other novel genes in estrogen metabolism and several major genes in the pathways of angiogenesis, extracellular matrix remodeling, inflammatory response, and prostaglandin synthesis. These genes are involved in regulating the tumor microenvironment and are likely related to, not only the prognosis, but also the risk of cancers large enough to be detected clinically. The proposed study will use data and biological samples collected from the Shanghai Breast Cancer Study (RO1CA64277). Genetic polymorphisms in approximately 25 candidate genes will initially be evaluated using both genotype- and haplotype-approaches in approximately 1200 cases and 1200 controls recruited from 1996 to 1998. Promising associations identified in the initial phase will be re-evaluated in the second set of subjects (1300 cases and 1300 controls) recruited since 2002 in the parent study. This 2-phase study design will effectively balance both Type I and Type 2 errors and provide credible results towards our understanding of the etiology of breast cancer. Results from this study will be valuable in identifying high risk women for primary and secondary prevention of breast cancer. Funded by the National Cancer Institute Investigators: Wei Zheng, M.D., Ph.D. (PI); Xiao Ou Shu, M.D., Ph.D.; Qiuyin Cai, Ph.D., M.D.; Jirong Long, Ph.D.; Jay H. Fowke, M.P.H., Ph.D.; Shimian Qu, Ph.D.; Chun Li, Ph.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. National Children’s Study This proposal is offered by the Davidson Partners for Children’s Health, a collaborative formed to seek and facilitate large-scale research that will advance maternal and child health. The Partners include community and academic care providers; all six childbirth facilities in the county; stakeholder organizations; related government offices; and resources such as a media liaison. As a study center we will 1) provide center leadership and senior staff who are experienced researchers skilled at effectively leading large scale enterprises, are trusted in the community, and will have longevity with the study; 2) establish a high-performing study center that can agilely draw on the experience of the entire local organizational structure to efficiently plan, implement, tailor, and launch the Davison study center; 3) serve the National Children´s Study (NCS) leadership and steering committee; assure timely and accurate data transfer and reporting to the NCS-CC; and share lessons-learned with the larger NCS study community; 4) fully integrate expertise and staffing capabilities to deploy an exceptionally well-prepared field operations team for recruitment, household visits, and data and specimen collections; 5) initiate study activities on schedule and precisely implement all aspects of study protocol, including sample evaluation with adjustments as needed to achieve enrollment of 1,000 mother-child dyads; 6) achieve top performance in tracking and retaining participants in follow-up; and 7) dedicate ourselves to participant satisfaction, successful community engraftment, and the highest ethical standards as steward of the national reputation and visibility of the NCS. Funded by the National Institutes of Health Investigators: Katherine E. Hartmann, M.D., Ph.D. (PI); Judy Aschner, M.D.; Shari Barkin, M.D., M.S.H.S.; Gordon Bernard, M.D.; William Blot, Ph.D.; Clarence Creech, M.D., M.P.H.; Robert Dittus, M.D., M.P.H.; Elizabeth Dykens, Ph.D.; Kathryn Edwards, M.D.; Jonathan Gitlin, M.D.; Tina Hartert, M.D., M.P.H.; Elizabeth Heitman, Ph.D.; Lynne Hutchison, B.S.; Howard Jones, M.D.; Yvonne Joosten, M.P.H.; Lynda Lane, R.N.; Melanie Lutenbacher, Ph.D.; Russell Rothman, M.D.; Charles Rush, M.D.; Glynis Sacks, M.D.; David Schlundt, Ph.D.; Martha Shrubsole, Ph.D.; Paul Speer, Ph.D.; Wendy Stone, Ph.D.; Richard Urbano, Ph.D.; Deborah Wage, M.S.N., F.N.P., C.N.M.; Allison Woodworth, Ph.D. Shanghai Breast Cancer Study (renewal) Breast cancer is the most common malignancy among women in the United States and many other parts of the world. It is believed that most breast cancers are caused by genetic factors and environment interactions. Over the past 10 years many genetic polymorphlsms have been investigated in relation to breast cancer risk, yet few of the associations found have been confirmed. As part of this renewal application for the Shanghai Breast Cancer Study (SBCS R01CA64277), a large population-based case-control study of breast cancer funded by NCI since 1996, we propose several novel approaches to circumvent the limitations of the methodologies currently used for studying low-penetrance genetic variants for the risk of complex, multifactorial diseases. First, in addition to studying common genetic variants using haplotype tagging SNPs (htSNP), we propose to test the hypothesis that a large part of breast cancer susceptibility may be due to the summation of the effect from multiple low-frequency genetic variants. We also propose to use re-sequencing data to enhance htSNP selection and reduce misclassification errors and use quantitative functional data to define risk groups. With these new approaches, we will comprehensively evaluate genetic polymorphisms in the TGF2 signaling pathway in a two-phase study including approximately 6,200 cases and controls. Genetic variants in major TGF2 pathway genes will be screened in Phase I, and promising associations will be validated in Phase II along with a series of in vitro functional assays. Breast cancer patients are being followed for cancer recurrence, relapse, and death, and the association of TGF2 pathway gene variants with breast cancer survival will be evaluated in a two-phase study. Numerous in vitro and animal studies have clearly demonstrated that the TGF2 signaling pathway plays a pivotal role in the development and progression of breast cancer. It remains unclear, however, whether these laboratory findings can be translated into cancer prevention strategies and clinical practice. The proposed study, with its strong methodology and novel approaches, has outstanding potential for discovering genetic markers that will be valuable in identifying high-risk women for cost-efficient breast cancer prevention and personalized treatment and follow-up care after cancer diagnosis. The proposed novel approaches will not only facilitate the evaluation of the study hypotheses, but also provide significant data to expand and guide future studies of low-penetrance genetic factors for breast cancer and other complex, multifactorial diseases. Funded by the National Cancer Institute Investigators: Wei Zheng, M.D., Ph.D. (PI); Xiao Ou Shu, M.D., Ph.D.; Qi Dai, M.D., Ph.D.; Qiuyin Cai, Ph.D., M.D.; Jirong Long, Ph.D.; Chun Li, Ph.D. Shanghai Breast Cancer Study This is an ongoing study funded since 1996 to investigate genetic and lifestyle factors as well as other biomarkers for breast cancer risk and survival. Almost all epidemiologic studies of breast cancer have been conducted in Western populations with homogeneous and high exposure to certain hypothetical risk factors; the narrow range of exposure has substantially reduced efficiency in these studies. A population based case-control study is proposed among Chinese women in Shanghai where the incidence rate of breast cancer has increased dramatically in the past two decades. The investigators state that the unique lifestyle pattern and diverse exposures in this population will facilitate a rigorous examination of some important etiologic hypotheses that cannot be adequately addressed among women in the United States. The primary aims of this study are to investigate the associations of breast cancer with dietary fat intake across the range 14% to 36% of calories (median of lowest to highest quintile), nutritional status during adolescence (including adolescent diet and certain anthropometries), estrogen metabolic pattern, body mass and fat distribution, oral contraceptive use, induced abortions, and breast feeding. The study will include a total of 1200 incident breast cancer cases aged 25-64 and an equal number of controls (frequency matched to cases on age) randomly selected from the general population in Shanghai. Cases will be identified through two well tried rapid case finding systems and the population based Shanghai Cancer Registry. In person interview data, anthropometric measurements and fasting blood and urine will be collected. For 500 pairs of cases and controls, urine samples will be assayed for levels of 2 and 16-alpha hydroxyestrones. Tumor tissue blocks will be collected for assays of estrogen and progesterone receptors to assess whether receptor defined subgroups of breast cancer are etiologically distinct. The remaining biospecimens will be stored at -70C for future molecular epidemiologic studies of serum organochlorine pesticides, somatic mutations in tumor tissue, genotypes of HRAS and certain metabolizing enzymes using DNA from white blood cells and other biomarkers. The investigators state that this study will provide valuable information on the interplay of hormonal, genetic, dietary, environmental, and lifestyle factors in the development of breast cancer. They further state that it will also create a valuable resource for future studies of genetic factors and gene-environmental interaction in the etiology of breast cancer. Funded by the National Cancer Institute Investigators: Wei Zheng, M.D., Ph.D.(PI); Xiao Ou Shu, M.D., Ph.D.; Qi Dai, M.D., Ph.D.; Qiuyin Cai, Ph.D., M.D.; Jirong Long, Ph.D.; Chun Li, Ph.D. Shanghai Endometrial Cancer Study (SECS) Estrogen plays a central role in the etiology of endometrial cancer. The association of exogenous estrogen use and high endogenous hormone exposure with endometrial cancer has been well characterized. The effect of soyfoods, rich source of phytoestrogens that have both weak estrogenic and anti-estrogenic effects, has only been studied in two studies and results were inconsistent. Given the dual effect of phyotoestrogens, we hypothesize that the effect of phytoestrogens on endometrimum depends on the levels of endogenous estrogens. The level and biological effect of estrogens are determined by multiple genes and thus the risk of endometrial cancer may be associated with genetic polymorphisms of genes involved in estrogen biosynthesis, metabolism, binding and signaling, and their joint effect with soyfood intake and other lifestyle factors. To evaluate the above hypotheses, we propose to conduct a population-based case-control study including 1150 incident cases and 1150 age-matched controls in urban Shanghai. In-person interviews will be conducted to collect dietary and other exposure information. A 10-ml peripheral blood sample (or a buccal cell sample if blood sample could not be obtained) will be collected from all cases and controls. Genomic DNA will be analyzed for the genotypes of the genes involved in estrogen biosynthesis (CYPI7, CYP19, and HSD17B1), inactivation (SUTL1AI, UGT1, and COMT), binding (SHBG), and signal transduction (ER-a and ER-b). Associations of endometrial cancer with soyfood intake and polymorphisms of above-mentioned genes will be evaluated separately, jointly and in conjunction with conditions related to estrogen levels (e.g., obesity, physical activity, dietary fat intake, and menopausal status). Incidence rate and prevalence rates of traditional risk factors (e.g., estrogen replacement therapy, obesity, nulliparity) of endometrial cancer are considerable low among women in Shanghai than their counterparts in the US, and this will minimize potential confounding effects in testing new hypotheses. Consumption level of soyfood is high and hysterectomy rates are extremely low among Chinese women, providing a unique opportunity to test the hypotheses posed in the application that are difficult to be evaluated in the U.S. population. Funded by the National Cancer Institute Investigators: Xiao Ou Shu, M.D., Ph.D. (PI); Wei Zheng, M.D., Ph.D.; Qi Dai, M.D., Ph.D.; Wanqing Wen, M.D.; Qiuyin Cai, M.D., Ph.D.; Jirong Long, Ph.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. Tumor Markers and Recurrent Adenomas: A Follow-up Study Most colorectal cancers arise from adenomatous polyps, and a large proportion of patients with adenomas will develop recurrent adenomas. There is considerable controversy regarding the appropriate surveillance interval following initial colonoscopy. Studies assessing predictors for recurrent adenomas will provide valuable information for designing individualized surveillance strategies, particularly for patients with either multiple adenomas or pathologically advanced adenoma. We propose in this application to recruit and follow 2000 patients diagnosed in 1996 to 2001 with incident multiple or advanced adenomas to evaluate the utility of a panel of promising tumor markers in predicting the risk of adenoma recurrence. The tumor markers proposed for this study reflect major events that occur during the formation and progression of adenomas. Specifically, we will evaluate the following four groups of tumor markers in relation to the risk of adenoma recurrence: 1) proliferation and apoptosis, including the apoptosis index (TUNEL assay) and the expression of Ki-67 (Mibl), epidermal growth factor receptor (EGFR), and transforming growth factor B receptor type II (TGF-J3 RI]); 2) genomic instability - loss of heterozygosity (LOH) events on chromosomes 5q, l7p, 15q, ip, and 18q; 3) Wingless/Writ signaling pathway - expression of the CTTNB1 (Beta-catenin gene), Cyclin D1 CMYC, and COX2 gene products; and 4) DNA methylation - methylation status of the promoters of the MLH1, MGMT, CDKN2A/P16, and APC. Study patients will be followed through a combination of telephone interviews and medical chart reviews. Paraffin-embedded blocks of initial adenomas will be retrieved for bioassays of tumor markers. The diagnosis of initial and recurrent adenomas will be reviewed and confirmed by study pathologists. This study is likely to provide valuable information for identifying high-risk adenoma patients for close surveillance and chemoprevention. Funded by the National Cancer Institute Investigators: Wei Zheng, M.D., Ph.D. (PI); Reid M. Ness, M.D.; Martha J. Shrubsole, Ph.D; Walter E. Smalley, M.D., M.P.H.; Kay Washington, Ph.D., M.D.; Bill Grady, M.D.; Ayumi Shintani, Ph.D., M.P.H.; Robert Dittus, M.D., M.P.H.