IMPH Research in Genetic and Molecular Epidemiology

Consortium Study to Identify Breast Cancer Susceptibility Loci 
Developing Statistical Methods for Disease Gene Discovery 
Dietary Calcium and Magnesium, Genetics, and Colorectal Adenoma 
Epidemiologic Architecture for Genes Linked to Environment (EAGLE) 
Epidemiology of Molecular Risk Factors for Breast Cancer 
Exome Sequencing to Identify Novel Genetic Factors for Lung Cancer in Nonsmokers 
Fatty Acid Desaturase Activity, Fish
Oil and Colorectal Cancer Chemoprevention 
Gene and Environment Interaction and Insulin Resistance 
Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer 
Genetic and Epigenetic Markers for Colorectal Adenoma Recurrence 
Genetic Factors for Breast Cancer: A
Genome Wide Study 
Genome Sequencing to Identify Novel Genetic Factors for Breast Cancer Risk 
Genome-Wide Copy Number Variation and Breast Cancer Risk 
Helicobacter Pylori Blood Biomarker for Gastric Cancer Risk in East Asia 
Modifiable Risk Factors for Fatal Prostate Cancer: A Prospective Study in Asia 
Molecular and Cellular Basis for the Efficacy of Bariatric Surgery 
A Multi-Center Epidemiologic Study of Breast Cancer in African-American Women
Prognosis of Lung Cancer: Heredity or Environment? 
Returning Research Results of Pediatric Genomic Research to Participants 
Shanghai Breast Cancer Study (SBCS) 
Shanghai Endometrial Cancer Study (SECS) 
Shanghai Men's Health Study 
Southern Community Cohort Study 
Understanding the Genetic Risk Underlying Racial Disparities in Uterine Fibroids 
Vitamin D Status, Gene
Polymorphism and Breast Cancer Progression/Prognosis

Consortium Study to Identify Breast Cancer Susceptibility Loci

Breast cancer is the most common malignancy among women in the United States and many other parts of the world. Genetic factors play an important role in the etiology of breast cancer. Recent genome-wide association studies (GWAS) have identified multiple genetic susceptibility loci for breast cancer. However, these newly- identified genetic factors, along with high-penetrance susceptibility genes reported previously (such as the BRCA1 and BRCA2 genes), explain only a small fraction of genetic variation for breast cancer. In this application, we propose two novel projects that will significantly advance our understanding of the genetic basis for breast cancer and the methodology used for genetic epidemiologic research. The first project is a GWAS based on the newly-established Asia Breast Cancer Consortium and will include over 27,000 cases and controls recruited from 11 studies conducted among Asian women living in various parts of the world. Through analyzing GWA scan data from 3,500 cases and 3,500 controls, we will identify and evaluate the top 8,500 SNPs in an independent set of 3,500 cases and 3,500 controls and then validate approximately the top 100 SNPs in 6,700 cases and 6,700 controls. In the second project, we will sequence eight GWAS-mapped regions in 3,000 cases and 3,000 controls with the goal of identifying additional genetic risk variants, particularly low- frequency variants, for breast cancer in these regions. We will select up to 180 promising SNPs for replication in an independent set of 2,500 cases and 2,500 controls and then select the top 30 SNPs for further evaluation in another independent set of 2,500 cases and 2,500 controls. This is the only well-powered GWAS conducted in Asian women, and thus is the only existing GWAS capable of discovering genetic variants for breast cancer that are unlikely or more difficult to identify in other GWAS. The proposed sequencing project represents a new model for future genetic association studies. These two newly-proposed projects will be built upon several well- conducted, NCI-funded studies to generate substantial novel information that will help to not only understand breast cancer biology and genetics, but also to improve risk assessment models and identify high-risk women for cost-efficient prevention of breast cancer. Read more.

Funding Source: NIH/NCI 
PI: Wei Zheng

Developing Statistical Methods for Disease Gene Discovery

Human genetics research has accelerated in the last decade owing to our evolving understanding of the human genome. With the recent completion of the International HapMap Project, the development of largescale genotyping technology, and rapid decline in genotyping costs, an immense amount of genotype data have been generated, which in turn raises many new challenging problems for analysis and interpretation of the data. This application proposes developing new statistical methodologies that aim to address a wide range of statistical issues in current candidate gene and genome-wide association (GWA) studies. Specifically, the proposal will address the following problems. (1) Recent high-resolution genome mapping indicates that copy number variations (CNVs) are ubiquitous and common in the general population, and may play a major role in phenotypic variation. In Aim 1, we will develop a Bayesian hidden Markov model based algorithm for highresolution CNV detection using whole-genome SNP genotyping data. Our algorithm has the ability to incorporate both unrelated individuals and family data. (2) Given the high density of genetic markers in largescale candidate gene and GWA studies, it is reasonable to expect that multilocus genotypes offer more information on genetic association than single-marker analysis. In Aim 2, we will develop a powerful multimarker test for gene-based association analysis and extend the method to analysis of gene-gene interactions. The virtue of our method lies in its ability to borrow strength from nearby markers while reducing the degrees of freedom. (3) In many disease gene-mapping studies, individuals are ascertained from a recently admixed population. In Aim 3, we will develop novel association tests in genetics studies using recently admixed populations. By considering ancestry level and genotypes together, our method offers higher resolution and power than traditional admixture mapping methods. (4) Appropriate adjustment for multiple dependent tests has long been a problem in genetics studies, especially for studies with limited sample size and without replication datasets. In Aim 4, we propose new methods to estimate the effective number of tests that reflect the amount of independent information contained in the data. (5) In Aim 5, we will develop, test, distribute, and support freely available implementations of the methods proposed in this application. The methods will be evaluated through analytical approaches, computer simulations and applications to multiple real datasets. Recent development of large-scale genotyping technologies has led to the generation of an immense amount of genotype data, which raises many new challenging problems for the analysis and interpretation of the data. This application proposes developing new statistical methodologies that address a set of unresolved issues. Read more.

Funding Source: NIH/NHGRI
PI: Li Chun

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 very 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, based on our promising data, 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 fortication to prevent occurrence of colorectal adenoma, and, thus, colorectal cancer. In the general US 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 very 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. Read more.

Funding Source: NIH/NCI 
PI: Qi Dai

Epidemiologic Architecture for Genes Linked to Environment (EAGLE)

With the advent of the Human Genome Project, the International HapMap Project, and high-throughput yet cost-effective genotyping, it is now possible to interrogate the human genome with >1 million markers for associations with common human diseases and traits. Within the last few months, the literature has become inundated with reports of genome-wide association (GWA) studies identifying new genetic variations associated with phenotypes of public health interest. While the flurry of discovery is exciting, the usefulness of these new findings in a general population setting remains unclear. Therefore, the next steps beyond the initial GWA studies must provide population-based data on these initial associations before the most promising findings can be translated into improvements in intervention, prevention, and/or treatment options for the general population. The genetic component of the National Health and Nutrition Examination Surveys (NHANES; n~20,000) can provide the data necessary to move beyond the initial GWA study discoveries. NHANES is a U.S. population-based, cross-sectional survey collected by the Centers for Disease Control and Prevention. NHANES DNAs are linked to demographic, health, lifestyle, laboratory, extensive clinical, and physical examination data for participating individuals. Because participants are ascertained regardless of health status, NHANES is a rich resource for phenotypes (clinical endpoints and quantitative traits) and environmental exposures. With this large dataset, the epidemiologic architecture of GWA-identified genetic variations will be described, and association studies will be conducted to provide more accurate effect size estimates and population attributable fractions for many common diseases and traits such as type 2 diabetes, obesity, and coronary artery disease. Finally, tests for gene-environment and nuclear mitochondrial gene interactions will be performed, the latter of which laboratory data will be generated to support the statistical association. The purpose of this grant is to provide evidence in population-based datasets that GWA-identified genetic variations are relevant to most people. As such, GWA-identified variations will be characterized and population-based statistics and data for modifiers of these variations will be released rapidly so that the most promising findings can be incorporated into future translational studies by the research community. Read more.

Funding Source: NIH/NHGRI 
PI: Dana Crawford

Epidemiology of Molecular Risk Factors for Breast Cancer

We are conducting a whole-exome sequencing study to systematically search the entire coding region in the human genome to detect lung cancer susceptibility genes and variants. This study is built on the resources established in the Shanghai Women’s Health Study, Guangzhou Lung Cancer Study, and the Female Lung Cancer Consortium in Asia, all of which are conducted among East-Asian women. The specific aims of the study are as follows; all cases and controls are female never-smokers. Aim 1 is to sequence the whole exome of 600 NSCLC cases and 600 controls (Stage 1). Aim 2 is to validate variants in approximately 350 promising genes identified in Aim 1 in 2,500 NSCLC cases and 2,500 controls (Stage 2). Aim 3 is to validate approximately 15 genes from Stage 2 in an additional 2,500 NSCLC cases and 2,500 controls (Stage 3). To our knowledge, this is the first large association study of lung cancer conducted among never-smokers using whole-exome sequencing. Read more.

Funding Source: NIH/NCI 
PI: William Dupont

Exome Sequencing to Identify Novel Genetic Factors for Lung Cancer in Nonsmokers

Lung cancer is the leading cause of cancer death in the United States and many other countries. Genetic factors play an important role in the etiology of lung cancer. Recent genome-wide association studies (GWAS) have identified multiple genetic susceptibility loci for lung cancer. However, these newly-identified genetic factors explain only a small fraction of the heritability for lung cancer. Moreover, these studies were conducted primarily among smokers, raising the possibility that the identified associations could be related to tobacco use behavior, lung carcinogenesis, or both. Genetic studies conducted among never-smokers provide exceptional opportunities to discover genetic variants that confer risk for lung cancer independent of smoking. Recently evidence has emerged to strongly suggest that most of the heritable risk for cancer and other complex diseases may be due to a large number of low-frequency, moderate-penetrance genes. Herein, we propose a whole-exome sequencing study to systematically search the entire coding region in the human genome to detect lung cancer susceptibility genes and variants that cannot be identified through conventional GWAS or family-based linkage analyses. The proposed study will be built on the resources established in the Shanghai Women's Health Study, Guangzhou Lung Cancer Study, and the Female Lung Cancer Consortium in Asia, all of which are conducted among East-Asian women. The specific aims of the study are as follows; all cases and controls are female never-smokers. Aim 1 is to sequence the whole exome of 600 NSCLC cases and 600 controls (Stage 1). Aim 2 is to validate variants in approximately 350 promising genes identified in Aim 1 in 2,500 NSCLC cases and 2,500 controls (Stage 2). Aim 3 is to validate approximately 15 genes from Stage 2 in an additional 2,500 NSCLC cases and 2,500 controls (Stage 3). To our knowledge, this is the first large association study of lung cancer conducted among never-smokers using whole-exome sequencing. With its strong methodology and use of novel technologies and study design, the proposed study will significantly improve our understanding of lung cancer genetics and biology through the identification of novel genes and pathways. Newly-identified genes and pathways could serve as targets for novel cancer treatments, and genetic variants from these genes could be used for cancer screening and risk assessment aimed at identifying high-risk individuals for targeted lung cancer prevention. Read more.

Funding Source: NIH/NCI 
PI: Qiuyin Cai

Fatty Acid Desaturase Activity, Fish Oil and Colorectal Cancer Chemoprevention

Observational studies have suggested that the n-3 polyunsaturated fatty acids, eicosapentanoic acid and docosahexanoic acid, may reduce the risk of colorectal cancer. Our hypothesis is that individuals with lower activity of fatty acid desaturase-1(FADS1) will derive greater benefit from fish oil supplementation than individuals with higher FADS1 activity due to lower production of endogenous arachidonic acid. To test this hypothesis we will recruit 150 participants and conduct a 6-month double blind 3 X 2 factorial randomized controlled trial. Our first factor will be FADS1 genotype (GG, GT, and TT) and our second factor will be fish oil supplementation (fish oil versus placebo). Our specific aims include: 1) to determine the efficacy of fish oil supplements on rectal epithelial cell proliferation indexes and markers of rectal crypt apoptosis, and 2) to determine the effect of genetically-determined fatty acid desaturase 1 activity on fish oil supplementation for colorectal cancer chemoprevention. Read more.

Funding Source: NIH/NCI
PI: Harvey Murff

Gene and Environment Interaction and Insulin Resistance

Type 2 diabetes (T2D) affects more than 20 million people in the US, and its prevalence is increasing. Insulin resistance is a necessary condition for T2D to develop and results from an interaction between genetic and environmental factors. Understanding factors associated with insulin resistance and its genetic controls is of particular importance for the prevention of T2D, because insulin resistance is reversible. Major environmental risk factors for insulin resistance include obesity, central obesity, low physical activity, and dietary factors. Among dietary factors, dietary fat plays an important role in the induction of insulin resistance. The etiology of insulin resistance could derive from defects between insulin receptors and glucose transporter 4, and defects in the insulin receptor substrate may be a central feature of insulin resistance. However, there is limited evidence about the role of gene variants in the insulin-signaling pathway and prevalence of T2D or insulin resistance. Recent genome wide association studies (GWAS) have only identified a few new genes that appear to influence insulin resistance. This could be due to the failure to examine how environmental factors affect genetic susceptibility in the development of insulin resistance and/or T2D. In the proposed application we will explicitly evaluate the association of genetic polymorphisms in the first three genes in the insulin signaling pathway (the insulin receptor, INSR, and insulin receptor substrates 1 and 2, IRS1 and IRS2), glucose transporter 4 (GLUT4), and genes identified from GWAS of T2D quantitative traits with insulin resistance in the context of gene-environment interactions. Using fasting insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) as proxies, we will analyze existing clinical and demographic data from 2000 non diabetic male participants of an ongoing, population-based prospective study conducted in Shanghai, China, for whom dietary factors, physical activity, anthropometric variables, and fasting glucose and insulin have already been measured. The goals of the proposed project are in concert with the parent K01 application's goal to determine gene-diet and gene-physical activity interactions associated with T2D. This application expands the overall goal of the K01 award by extending research in this important area of investigation to the study of quantitative traits associated with insulin resistance. Findings from this study can be used to aid in the prevention of T2D, since insulin resistance is a reversible condition. Read more.

Funding Source: NIH/NIDDK
PI: Raquel Villegas

Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer

The purpose of this study is to investigate the associations between obesity, prostate cancer, and high-grade prostatic intraepithelial neoplasia (PIN). Toward this goal, we developed a multi-centered rapid-recruitment protocol targeting men seeking a diagnostic prostate biopsy within any urology clinic in metro Nashville, TN.  Trained staff measure body size and body composition using bioelectric impedance analysis, collect pre-diagnosis blood and urine for biomarker and genetic analyses, administer a research lifestyle questionnaire, and perform medical chart review for clinical and pathology data.  Genetic and molecular markers of obesity are investigated toward prostate cancer and PIN risk. Read more.

Funding Source: NIH/NCI 
PI: Jay Fowke

Genetic and Epigenetic Markers for Colorectal Adenoma Recurrence

Most colorectal cancers arise from adenomatous polyps, and a large proportion of adenoma patients develop new (metachronous) adenomas after their initial polypectomy. There is considerable controversy regarding an appropriate surveillance interval for adenoma patients after removal of their initial adenomas. We propose to conduct a follow-up study to evaluate both genetic susceptibility risk variants and tumor markers in relation to the risk of metachronous adenomas. The proposed study will be conducted in approximately 1,500 patients diagnosed with either multiple adenomas or a pathologically advanced adenoma. These patients have already been recruited in our previous studies. In addition to clinical and epidemiologic data, we have already obtained germline DNA samples, fresh-frozen polyp tissues, and formalin-fixed, paraffin-embedded (FFPE) from a large proportion of study participants. In this study, we propose to: 1) follow up with study participants to collect information related to follow-up exams and adenoma recurrence and to obtain FFPE blocks of initial adenomas from the remaining patients whose samples have not yet been collected 2) evaluate the association of genetic and epigenetic tumor markers with recurrent adenomas 3) evaluate the association of adenoma recurrence with GWAS-identified genetic variants 4) establish a risk-assessment model and evaluate the utility of genetic susceptibility and tumor markers alone and in combination with known predictors (such as pathologic features of initial adenomas) in predicting the risk of adenoma recurrence. This proposed study will provide critical information that is valuable to identify high-risk adenoma patients for intensive follow-up programs and chemoprevention. Read more.

Funding Source: NIH/NCI 
PI: Harvey Murff

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 (RO1 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 1500 cases and 1500 controls. All promising SNPs will be further validated using data from 1000 cases and 2000 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 the study will be valuable in identifying high risk women for primary and secondary prevention of breast cancer. Read more.

Funding Source: NIH/NCI 
PI: Wei Zheng

Genome Sequencing to Identify Novel Genetic Factors for Breast Cancer Risk

Genetic factors play an important role in the etiology of both sporadic and familial breast cancer, a complex, multifactorial disease. Known genetic risk factors identified to date, including both rare high- penetrance genes and common low-penetrance variants, explain only about 28% of heritability for breast cancer. Recently emerged evidence strongly suggests that most of the heritable risk for breast cancer and other complex diseases may be due to a large number of low-frequency moderate-penetrance genes that are difficult to identify using conventional family-based linkage analyses and genome-wide association studies (GWAS). In this application, we propose a novel study to systematically search for the entire coding region in the human genome to identify new genetic susceptibility factors for breast cancer. This study will be built upon the resources we established in three NCI-funded large epidemiologic studies conducted among women in Shanghai, in which genomic DNA samples and comprehensive clinical and epidemiological data were collected from nearly 8,000 breast cancer cases and a large number of community controls. Specifically, we propose to sequence the whole exome for 600 genetically-enriched breast cancer cases and 600 controls (Stage 1). Using data from Stage 1 and those from the 1000 Genomes Project, we will select approximately 350 promising genes for replication through variant genotyping (Stage 2) in an independent set of cases and controls. Approximately 20 genes will be selected for Stage 3 replication from those that show promising association in Stage 2 but require additional evaluation to either confirm or reject the hypotheses. To our knowledge, this is the first large association study for breast cancer using whole exome sequencing. With strong methodology and the use of novel technology and study design, the proposed study will identify novel genes and pathways that will significantly improve our understanding of breast cancer genetics and biology. Newly identified genes, particularly those with a substantial effect size, could serve as targets for novel cancer treatment and be used for cancer screening and risk assessment. Read more.

Funding Source: NIH/NCI 
PI: Wei Zheng

Genome-Wide Copy Number Variation and Breast Cancer Risk

This is an expedited resubmission of a grant application, a genome-wide copy number variation study of breast cancer (R01CA137013). Breast cancer is the most common malignancy among women in the United States and many other parts of the world. Genetic factors play an important role in the etiology of breast cancer. Single nucleotide polymorphisms (SNPs) were thought to be the predominant form of genomic variation and were commonly used as genetic markers in genetic association studies. Over 100 candidate genes have been investigated in relation to breast cancer risk, however, only a few of them, have been replicated. Recently, genome wide association (GWA) studies have identified novel genetic risk factors for this common malignancy. However, it is unlikely that SNP markers could entirely explain genetic variation for breast cancer as other important genetic variations exist. Recently, large DNA fragment duplication and/or deletion, termed as copy number variation (CNV), has been shown to frequently occur in the human genome. CNVs account for more nucleotide variation than SNPs and they may be an unrecognized source of breast cancer genetic susceptibility. Strong associations between CNVs and human diseases are increasingly reported such as familial breast cancer, pancreatic cancer, prostate cancer, autism, etc. We propose to survey the entire human genome for CNVs associated with breast cancer. The multi-phase CNV GWA proposed in this application will be built upon the resources established in three large, on-going studies funded by NCI, a recently supported `Genome-wide association study for breast cancer (R01 CA124558), the Shanghai Breast Cancer Study (R01 CA64277) - a population-based case-control study, and the Shanghai Women's Health Study (RO1 CA70867) - a population-based prospective cohort study. In Phase I, we will conduct a genome wide CNV scan in 1,353 cases and 1,349 controls. We have recently completed Stage I genotyping for 1,353 cases and 1,349 controls by using Affymetrix 6.0 array as part of an existing SNP GWA study (RO1 CA124558). Intensity data from around one million SNPs and one million non-polymorphic probes included in the array for these 2,702 samples will be available for this proposed study to call CNVs. Associations of these CNVs with breast cancer risk will be investigated. In Phase II, the 500 most promising CNVs will be selected for validation in an independent sample of 1,500 cases and 1,500 controls. In Phase III, the most promising 30 CNVs will be further validated in 1,000 cases and 2,000 controls selected from the prospective SWHS. The parent projects of this newly-proposed study have been exceptionally well-conducted with a strong methodology. The study is unique and has many unique features that facilitate a rigorous evaluation of breast cancer genetic factors. The results from the study will be valuable in identifying high risk women for primary and secondary prevention of breast cancer. Because Phase I data and specimen collection are supported by the existing studies and the use of a multi-phase study design, this project will be very efficient. Read more.

Funding Source: NIH/NCI 
PI: Jirong Long

Helicobacter Pylori Blood Biomarker for Gastric Cancer Risk in East Asia

Infection with Helicobacter pylori is the leading risk factor for gastric cancer, the second-most deadly and fourth-most common cancer in the world, yet only a fraction of those infected will develop the disease. Utilizing novel H. pylori multiplex serology in a nested case-control study in China, we have recently found a novel biomarker panel that could identify individuals with a 10-20% absolute risk of gastric cancer, and are now seeking to determine if we can replicate and validate this finding in other prospective cohorts in East Asia most likely to be infected with similar bacterial strains. As H. pylori eradication therapy can effectively reduce gastric cancer incidence and mortality, a validated risk prediction model in high-incidence populations will create the opportunity to substantially decrease the burden of gastric cancer through targeted prevention strategies among H. pylori-infected individuals at highest risk, while reducing unnecessary antibiotic use among those at low risk. Read more.

Funding Source: NIH/NCI 
PI: Meira Epplein

Modifiable Risk Factors for Fatal Prostate Cancer: A Prospective Study in Asia

Our overarching goal is to identify modifiable risk factors for fatal prostate cancer. Prostate cancer remains the second leading cause of cancer-death in the United States (U.S.), but known demographic and genetic risk factors have limited value in delaying progression. Further investigation in U.S. populations is problematic because widespread and selective prostate-specific antigen (PSA) testing is so strongly associated with the stage at diagnosis that any association between a risk factor and PSA testing could easily overwhelm a modest by important etiologic association. To remove this known detection bias, we propose a prospective investigation to determine the association between obesity, tobacco, and alcohol use with fatal prostate cancer using data from the Asian Cohort Consortium (ACC). Asian nations rarely perform PSA tests, and most prostate cancer patients in Asia are diagnosed with advanced or metastatic disease. The ACC is a unique resource that has harmonized data across 15 prospective cohort studies and includes over 450,000 men with approximately 3.5 million person-years follow-up. Prostate cancer is far less common in Asia than the U.S., and a prospective study would only be possible with such a consortium. Using a nested case- control design, each of the 507 recorded prostate cancer deaths to date will be individually matched to 10 controls by age (1 year) and cohort. Multivariable conditional logistic regression will be used to investigate associations between BMI, tobacco, and alcohol use with fatal prostate cancer. This project provides an exceptional opportunity to provide the first systematic prospective investigation of modifiable factors for fatal prostate cancer, while minimizing detection bias from selective PSA testing and subsequent treatment. Our results may form the basis for recommendations to prevent prostate cancer mortality in Asia, and more generally, in populations that are not routinely PSA-tested. Furthermore, results may also form the basis for adjuvant care recommendations among men diagnosed with localized disease by at risk for progression to an advanced stage and for death. Read more.

Funding Source: NIH/NCI 
PI: Jay Fowke

Molecular and Cellular Basis for the Efficacy of Bariatric Surgery

Bariatric surgery is currently the only effective treatment for severe obesity, and the only effective cure for type II diabetes. Research on the mechanism of action of the different bariatric surgical procedures in humans and model systems including pigs, dogs, rats, and mice supports the hypothesis that the beneficial effects result from more than the restrictive or malabsorptive effects of the procedures on food intake. Indeed, data argue that neuroendocrine changes in gut-brain signaling resulting from the Roux-en-Y and gastric sleeve procedures alter satiety, hunger, food preferences, and glucose homeostasis prior to the achievement of significant weight loss. Understanding the cellular and molecular basis of these changes induced by bariatric surgery might lead to the development of pharmaceutical interventions, or improved surgical procedures for the treatment of obesity and diabetes. While several animal models can be used for research on the physiology of bariatric surgery, the mouse provides the best model for studies of cellular and molecular mechanisms because transgenesis can be used to alter individual genes, and to label specific cell types. We show results here demonstrating successful creation of murine bariatric surgery models at Vanderbilt, and the use of the models to identify the first gene that plays an essential role in th efficacy of RYGB for long term maintenance of significant weight loss. The unique hypothesis to be tested is that the efficacy of bariatric surgery results not solely from a collection of changes to Gl signaling, but rather that essential changes in both Gl signaling AND in the plasticity and responsiveness of CNS homeostatic and hedonic circuits act synergistically to restore glucose homeostasis, and create a new weight set point. In this interdisciplinary team grant application, we bring together leading experts in human and murine bariatric surgery, murine pathology, Gl anatomy and function, obesity and diabetes, and quantitative human genetics to jointly study surgical preparations from humans and mice in order to identify the genes and cell types mediating the efficacy of bariatric surgery. Read more.

Funding Source: NIH/NIDDK
PI: Roger Cone

A Multi-Center Epidemiologic Study of Breast Cancer in African-American Women

Breast cancer, the most frequently diagnosed cancer among women, is the second leading cause of cancer death. Current breast cancer mortality rates in the United States, including Tennessee and South Carolina are considerably higher among African Americans than among Caucasians. Little is understood about the etiology of breast cancer nor do we know what factors might explain why African American women tend to be diagnosed with more aggressive disease than Caucasian women. Recent genome-wide association studies (GWAS) have opened opportunities to investigate breast cancer etiology. Approximately 20 susceptibility loci have been identified from the GWAS conducted among women of Chinese and European ancestry. Recent reports found breast cancer risk consistently increased among Caucasian and Chinese women with an increasing number of some of these loci. During the three years of this proposed project we anticipate an additional 15 to 20 susceptibility loci for breast cancer will be identified through GWAS, including our study conducted among Asian women. The relevance of these loci to African American women remains under-investigated, and data from our recent pilot investigation have showed that the majority of the initially-reported genetic risk variants identified in Caucasian and Chinese cannot be directly replicated among African Americans. The purpose of this proposed project is to investigate approximately 21 GWAS-identified loci to discover genetic risk variants relevant for African American women. In addition, we will establish a breast cancer risk assessment model that incorporates clinical and genetic factors to better identify high-risk African American women since the only existing breast cancer risk assessment model for African Americans does not include genetic markers. This full project will be supported by the Cancer Outreach Core. Read more.

Funding Source: NIH/NCI 
PI: Wei Zheng

Prognosis of Lung Cancer: Heredity or Environment?

This study seeks to find the reasons for poor survival after a lung cancer diagnosis, especially among people at greatest risk. Discovery of genes that affect lung cancer survival can identify new targets for drug treatments and lead to the development of important clinical tests to improve survival of lung cancer. Understanding the reasons for poor survival will lead to better quality of care and treatments for persons with lung cancer.

Funding Source: DOD
PI: Melinda Aldrich

Returning Research Results of Pediatric Genomic Research to Participants

The specific aim of this project is to determine what criteria should govern return of individual results of pediatric genomic research, using analysis of US law and international guidelines regarding decision making for and by minors as the foundation. This issue, which has received remarkably little attention, must be resolved if this research, which is vital to understanding the contributions of genetic variation to the health of children, is to proceed. In order to develop these criteria, it will be necessary to draw upon a host of ethical, legal, and sociocultural factors, using standard legal analytic tools. ¿ There is a long tradition within genetics, embodied in policy statements, such as those by the American Society of Human Genetics, the American College of Medical Genetics, and the American Academy of Pediatrics, of performing genetic tests on minors only when the results would alter the minor's immediate medical care. These limits are justified in part by the claim that, in the absence of need for immediate intervention, the minor should be allowed to decide about genetic testing upon reaching adulthood. ¿ More generally, decisions regarding the health care of children are treated differently from those of adults because children, as a matter of law, typically cannot make their own health care decisions. Procedurally, ethical and legal decision making authority, instead, is allocated among: 1) Parents who have broad authority to make choices among available options that affect their children. The scope of parental permission for their children's care, however, is not as broad as their discretion with regard to their own health care; 2) Clinicians who have an independent obligation to the welfare of the minor, which is bounded by the standards of clinical practice as well as legal requirements; 3) Minors who many hold have an increasingly important ethical and legal voice as they mature; and 4) In cases of abuse, neglect, or need to protect public health, the state. Substantively, defining the minor's best interest is often contested. One issue that is particularly challenging is deciding what weight should be given to various potential benefits from returning results, ranging from immediate benefit to the minor's health or reproductive information for the minor's later use to benefits that redound primarily to the family unit as a whole or exclusively to the parents or even to other minors of the same age or with the same condition. ¿ Research involving minors is subject to more legal and ethical requirements and limitations than apply to adults. This project brings together three internationally known lawyers, each of whom has written extensively about legal and policy issues in genomics research and in pediatrics, as well as an internationally known pediatrician- philosopher as a consultant, to define the applicable legal rules and to develop guidelines for returning results of genomic research involving minors. Read more.

Funding Source: NIH/NHGRI
PI: Ellen Clayton

Shanghai Breast Cancer Study (SBCS)

The Shanghai Breast Cancer Study (SBCS) is a population-based, case-control study funded by NCI since 1996 to investigate lifestyle factors, genetic susceptibility, and other biomarkers associated with breast cancer risk and survival. Included in the study are approximately 3,500 breast cancer cases aged between 25 and 70 years and an equal number of community controls recruited among female residents of Shanghai, China. In addition to in-person interview data, biological samples were collected from study participants. The resources from the study have supported multiple research and training grants and provided opportunities for many graduate students and postdoctoral fellows to conduct research. To date, over 150 research papers have been published from the SBCS addressing a wide range of significant issues related to dietary, lifestyle, environmental, and genetic contributions to breast cancer risk and prognosis.. Read more.

Funding Source: NIH/NCI 
PI: Xiao Ou Shu

Shanghai Endometrial Cancer Study (SECS)

The Shanghai Endometrial Cancer Study is a population-based, case-control study of 1,204 endometrial cancer cases and 1,212 controls who were aged between 30 and 69 years and recruited between 1997 and 2003. The study recently recruited an additional 587 endometrial cancer patients. The major objectives of the study are to evaluate the role of and interactions between hormonal, dietary, and other lifestyle factors and genetic susceptibility in endometrial carcinogenesis. In addition to detailed dietary intake and other questionnaire-based information, the study also collected a blood or buccal cell sample and a urine sample from participants. The study has published multiple papers reporting novel findings on dietary risk/protective factors and genetic susceptibility factors. The SECS is one of the largest epidemiological studies of endometrial cancer and is a major contributor to the international Epidemiology of Endometrial Cancer Consortium. Read more.

Funding Source: NIH/NCI
PI: Xiao Ou Shu

Shanghai Men's Health Study

The Shanghai Men’s Health Study (SMHS), funded by NCI since 2001, is a population-based cohort study of 61,482 men aged between 35 and 75 years and recruited from 2002 to 2006. At baseline, detailed information on dietary intakes, personal habits, occupational history, medical history, and other lifestyle factors was collected, and anthropometrics were measured. Blood or buccal cell, and  urine samples were collected from 89% of participants. The cohort has been followed through multiple in-person surveys to update exposure information and through record linkages with the population-based Shanghai Cancer Registry and Shanghai Vital Statistics Registry to obtain information on cancer occurrence and survival status. Over the years, SMHS data and biological samples have been used to evaluate many important etiologic hypotheses addressing the contributions of environmental, dietary, lifestyle, and genetic exposures to the development of cancer and other chronic diseases. The cohort supports multiple studies, including over 25 consortium projects. Read more.

Funding Source: NIH/NCI 
PI: Xiao Ou Shu

Southern Community Cohort Study

The second five-year renewal of the Southern Community Cohort Study (SCCS) is proposed in this grant application. Progress during the initial nine years of the study has been exceptional. We achieved a final cohort size of approximately 86,000 adults aged 40-79, two-thirds of whom are African American, with detailed baseline data assembled for all and biological specimens in frozen storage for nearly 90%. The cohort is now under follow-up for cancer mortality and incidence and other health outcomes. Historically, large-scale recruitment of African Americans, a group disproportionately burdened by cancer, into health research studies has been challenging. However, we uniquely overcame many known barriers to inclusion by developing partnerships with a network of southern Community Health Centers (CHCs), institutions that provide basic health services primarily to America's poor and uninsured. The SCCS thus differs from all other cohort studies in racial composition and socioeconomic disadvantage, and tracks a population possibly at higher cancer risk than any American population segment studied to date. Our specific aims for the renewal are (1) to continue passive follow-up of the cohort via linkages with various national and state registries to identify deaths, incident cancers and other health outcomes, (2) to continue active follow-up of the cohort via re-contact with participants to directly update exposure and health information, and (3) to conduct multiple new cohort and nested case-control analyses utilizing the baseline and follow-up data and stored DNA and blood specimens for evaluation of lifestyle, genetic and other risk or protective factors affecting the incidence of and disparities in the major cancers (lung, breast, prostate, and colon/rectum). We will evaluate hypotheses that the SCCS is uniquely or especially well positioned to address, many for the first time among African Americans, including the roles of obesity, vitamin D, specific infections (Chlamydia pneumoniae, Trichomonas vaginalis, Helicobacter pylori, and xenotropic murine leukemia virus-related virus), several nutrition-related pathways (one carbon metabolism, n-6 and n-3 polyunsaturated fatty acids and other dietary factors), cigarette mentholation, and use of the commonly prescribed glycemic control medication metformin, in relation to cancer risk and cancer disparities. Read more.

Funding Source: NIH/NCI
PI: William Blot

Understanding the Genetic Risk Underlying Racial Disparities in Uterine Fibroids

Fibroids affect 77% of women by onset of menopause in the U.S. and account for $9.4 billion in yearly healthcare costs. Until recently, tumor tissue and cell culture studies investigating fibroid growth have been the primary sources for understanding fibroid pathophysiology. In study we propose to identify genetic markers for risk of fibroids through a GWAS of African American and Caucasian participants, leveraging ancestral differences to narrow down genomic regions for targeted follow-up analyses. We will utilize BioVU, an electronic medical records database linked to DNA. Our first Aim is to conduct a GWAS for association between common SNPs and fibroid risk. Secondary admixture mapping analyses will be performed to identify chromosomal regions to prioritize for replication. Finally, in Aim 3 we will replicate SNPs associations in independent samples. This study represents the largest GWAS of fibroids and first among African Americans and leverages emerging technologies and new statistical approaches. Read more.

Funding Source: NIH/NICHD
PI: Digna R. Velez Edwards, PhD

Vitamin D Status, Gene Polymorphism and Breast Cancer Progression/Prognosis

The association of vitamin D deficiency, or low levels of circulating vitamin D, with increased risk for cancers, including breast cancer (BC), has received extensive attention. Experimental studies have shown that vitamin D has many anti-cancer properties, including anti-proliferative, anti-angiogenic, pro-apoptotic, and immunomodulation effects. Less attention has been paid to the role of vitamin D deficiency on BC prognosis and survival outcomes. Studies have shown that circulating vitamin D and polymorphisms in genes regulating vitamin D metabolism and signaling are both associated with BC risk, however, we know less about associations with BC prognosis. A few studies have linked low circulating vitamin D levels with prognostic factors for BC outcome, such as advanced disease or metastasis. Only one study directly evaluated the association between vitamin D status and BC survival, and no study has investigated this association in relation to vitamin D polymorphisms. We propose to address these questions in a prospective cohort of Chinese women with BC and test three hypotheses: 1) Circulating vitamin D level will predict BC progression and prognosis (recurrence, metastasis, overall or disease-specific death) after cancer treatment; 2) Genetic polymorphisms in vitamin D metabolism and signaling pathway genes affect circulating vitamin D level and its bioavailability in BC survivors; and 3) Circulating vitamin D and vitamin D gene polymorphisms together affect BC progression and prognosis. The proposed study will use resources from the Shanghai Breast Cancer Survival Study (SBCSS) and the Shanghai Breast Cancer Genome-Wide Association Study (GWAS). We will include 2,073 women newly-diagnosed with invasive BC and aged 20-74 years at the time of diagnosis, who have both blood samples for assessing circulating 25(OH)D and genotype information. Information on cancer diagnosis and conventional treatment, breast cancer recurrence, and causes of death will be verified through medical chart reviews. We will evaluate the effect of circulating vitamin D level and its combined effect with polymorphisms in the vitamin D pathway genes on BC progression and prognosis using appropriate statistical methods and controlling for known prognostic factors. The Mendelian Randomization (MR) method will be used to re-assess this association. Breast cancer survivorship is recognized as a critical component of cancer- related public health programs. The proposed study aims to fill a gap in our knowledge by evaluating the associations of circulating vitamin D and vitamin D pathway gene polymorphisms with breast cancer prognosis. This study will expand our understanding of the role of "Vitamin D status" and related pathway gene polymorphisms in BC prognosis. The study results could potentially lead to the development of new preventive and therapeutic strategies that can be applied to BC patients. In addition, the research could help determine if chemoprevention clinical trials with vitamin D should be considered for BC patients at high-risk for disease progression. Read more.

Funding Source: NIH/NCI 
PI: Xiao Ou Shu