Molecular and Genomic Epidemiology

Cancer risk reduction and diet: A cohort study of women 
PI:  Zheng, Wei      Funding Agency: NCI      Grant No.:  R37 CA070867 
Description: Using data and biological samples collected from the Shanghai Women’s Health Study (SWHS), we are evaluating several important etiologic hypotheses for cancer that are difficult to investigate in other existing cohort studies. We are studying dietary factors that could potentially reduce the risk of cancer. We also conduct nested case-control studies to evaluate biomarkers that could potentially be used for cancer risk prediction and assessment.

Colorectal cancerrisk loci: GWAS, fine-mapping, and functional analysis
PI: Zheng, WeiLong, Jirong     Funding Agency: NCI    Grant No.: R01 CA188214 
Description: Known genetic factors explain only a small fraction of colorectal cancer (CRC) heritability. This study cost-efficiently expands our ongoing genome-wide association study (GWAS) in East Asians to identify new genetic susceptibility loci for CRC.  We use fine-mapping and functional analysis to discover functional variants and genes that drive the associations. A novel stem-cell-driven mouse model of colonic neoplasia will be used to further determine specific CRC genes and susceptibility alleles in selected loci identified in GWAS. This GWAS expansion is the first large study in East Asians to comprehensively search for genetic risk factors for CRC. We anticipate identifying functional variants and novel genes/pathways for CRC to improve the understanding of the biological mechanisms through which GWAS-identified loci contribute to CRC risk. This information will help accelerate the translation of GWAS findings into disease prevention and treatment.

Common Genetic Variation and Quantitative Diabetes Traits
PI: Kabagambe, E. K.   Funding Agency: NCI  Grant No.: R01 DK78616 
In this study we seek to identify novel diabetes susceptibility genes in African American men and women and to determine whether genetic loci associated with type 2 diabetes in European Americans are transferable to African Americans. This work is done through the African American Glucose and Insulin Genetic Epidemiology (AAGILE) Consortium which includes data from over 16 cohorts and various electronic medical records including BioVU.

Consortium Study to Identify Breast Cancer Susceptibility Loci
PI:  Zheng, WeiLong, Jirong     Funding Agency: NCI      Grant No.:  R01 CA148667 
Description: This study comprises two projects to significantly advance our understanding of the genetic basis for breast cancer and the methodology used for genetic epidemiologic research. The first project, a genome-wide association study (GWAS) based on the newly-established Asia Breast Cancer Consortium, analyzes data from 11 studies conducted among Asian women living in various parts of the world.. In the second project, we sequence eight GWAS-mapped regions with a goal of identifying additional genetic risk variants, particularly low-frequency risk variants, for breast cancer. This is the only well-powered genetic study of its kind conducted in Asian women, and thus offers the opportunity to discover genetic variants for breast cancer that are unlikely or more difficult to identify in GWAS of other populations.

Exome Sequencing to Identify Novel Genetic Factors for Lung Cancer in Nonsmokers 
PI: Cai, Quiyin  Funding Agency: NCI  Grant No.: U01 CA161045 
Description: 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.
 
 
Fogarty International Clinical Research Scholars Support Center @ Vanderbilt-AAMC (FICRSF)
PI: Vermund, Sten     Funding Agency: FIC            Grant No.:  R24 TW007988 
Description: The goal of the program is to help train and inspire both US and foreign graduate students in research techniques and topic areas applicable to resource-limited and/or tropical countries.
 
 
Genetic and Endocrine Pathways Linking Obesity to Prostate Cancer  
PI: Fowke, Jay H.       Funding Agency: NCI           Grant No.: R01 CA121060 
Description: 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.
 
Genetic and epigenetic markers for colorectal adenoma recurrence
PI:  Zheng, Wei; Murff, Harvey     Funding Agency: NCI      Grant No.:  P50 CA095103 
Description:  This project was conducted as part of the Vanderbilt SPORE in GI Cancer (PI, Robert Coffey). Most colorectal cancers arise from adenomatous polyps, and a large proportion of adenoma patients develop new (metachronous) adenomas after their initial polypectomy. This study evaluates both genetic susceptibility risk variants and tumor markers in relation to the risk of metachronous adenomas. Approximately 1700 patients with multiple or advanced adenomas are included in this study. These patients are being followed for adenoma recurrence. Biological samples collected from these patients are being analyzed for genetic and epigenetic markers. It is anticipated that this study will provide critical information valuable in identifying high-risk adenoma patients for intensive follow-up.
 
Genetic Factors for Breast Cancer - A Genome-wide Study 
PI:   Zheng, Wei      Funding Agency: NCI      Grant No.:  R01 CA124558 
Description:   Genetic factors play an important role in the etiology of breast cancer.  With recent significant advances in high-throughput genotyping technologies, it has become feasible to conduct genome-wide association studies (GWAS) to systematically evaluate genetic risk factors for breast cancer. We initiated a pilot study in 2005 providing the proof-of-principle evidence that novel genetic risk variants for breast cancer can be identified in GWAS. This full-scale study, the first GWAS of breast cancer conducted in non-European descendants, initiated in 2008, uses resources of multiple studies. The results from the study will improve the understanding of breast cancer biology and genetics and could potentially be used to identify women at high risk for breast cancer.
 
Genome sequencing to identify novel genetic factors for breast cancer risk
PI:   Zheng, Wei        Funding Agency: NCI         Grant No.:  R01 CA158473 
Description:  Known genetic risk factors explain about 28% of heritability for breast cancer. Emerging evidence strongly suggests that a large fraction of the heritable risk for breast cancer and other complex diseases may be difficult to identify using conventional methods and genome-wide association studies (GWAS). This study systematically searches the entire coding region in the human genome to identify new genetic susceptibility factors for breast cancer. This is the first large association study for breast cancer using whole exome sequencing. It is anticipated that this study will identify novel genes and pathways to significantly improve our understanding of breast cancer genetics and biology. Newly identified genes could serve as targets for novel cancer treatment and improved cancer screening and risk assessment.
 
 
 
Nashville Breast Health Study
PI:  Zheng, Wei       Funding Agency: NCI         Grant No.: R01 CA100374 
This study is a population-based, case-control study of breast cancer conducted in Nashville, Tennessee since 2004. Its primary aim is to study genetic factors and gene-environment interactions in relation to breast cancer risk. Approximately 6,000 breast cancer cases and controls have been recruited; the vast majority of participants provided an exfoliated buccal cell or saliva sample as a source of genomic DNA. Breast tumor tissue samples have been collected from approximately 1400 participants with breast cancer. The main study ended in 2010. However, recruitment for breast cancer patients of African ancestry has been continued and expanded to other regions, including greater Tennessee, South Carolina and Georgia. Data and biological samples collected in this study have been used in multiple projects, including the first genome-wide association study of breast cancer in African Americans.
 
Polyunsaturated Fatty Acids and Colorectal Tumor Risk: A Molecular and Genetic Epidemiology Study
PI: Khankari, Nikhil            Funding Agency: NCI            Grant No.: K99 CA215360
Description: Arachidonic acid, a long-chain ω-6 polyunsaturated fatty acid (PUFA), has been demonstrated to affect carcinogenesis in animal and in vitro studies. The effect of arachidonic acid is believed to be largely due to overproduction of the eicosanoid, prostaglandin E2 (PGE2). The other class of PUFAs, ω-3, also bind to the same enzymes involved in arachidonic acid metabolism; however, the resulting set of eicosanoids are anti-inflammatory. Thus, ω-3 PUFA metabolism could indirectly inhibit PGE2 production and reduce cancer risk. Over the past few years, multiple genetic variants have been identified to be associated with PUFAs. The goal of this study is to elucidate the potential causal association between long-chain PUFAs and colorectal tumor risk using Mendelian randomization (MR), an approach that may avoid potential pitfalls of conventional observational epidemiologic research and utilizes genetic variation as a proxy for exposures.
 
Prognosis of lung cancer: heredity or environment?  
PI: Aldrich, Melinda     Funding Agency:  DOD     Grant No.: W18XWH-11-LCRP-EI 
Description:  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.
 
 
Shanghai Breast Cancer Study (SBCS)
PI: Zheng, Wei, Shu, Xiao Ou     Funding Agency: NCI            Grant No.: R01 CA090899R01 CA064277 
Description: 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.
 
 
Shanghai Men’s Health Study (SMHS) 
PI: Shu, Xiao Ou      Funding Agency: NCI        Grant No.: R01 CA082729UM1 CA173640 
Description: 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.
 
 
Shanghai Endometrial Cancer Study (SECS) 
PI: Shu, Xiao Ou        Funding Agency: NCI         Grant No.: R01 CA092585 
Description: 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.
 
 
Shanghai Women's Health Study (SWHS) 
PI: Zheng, Wei        Funding Agency: NCI         Grant No.:  UM1CA182910 
Description: This population-based prospective cohort study was initiated in 1996. From 1996 to 2000, approximately 75,000 Chinese women living in Shanghai were recruited into the study. In addition to survey data, most study participants donated blood (75%) and urine (87%) samples at baseline. Approximately 50% of study participants who did not donate a blood sample provided a sample of exfoliated buccal cells. This cohort of women is being followed for incidence of site-specific cancers and cause-specific mortality through a combination of in-person surveys and record linkages with population-based registries. Four in-person follow-up surveys have been completed, each with a response rate greater than 90%. The resources from this study have supported multiple studies, including approximately 40 international research consortia, to address etiologic hypotheses for cancers and other chronic diseases. The SWHS, with its large sample size, wealth of resources, and unique exposure patterns and disease spectrum, provides exceptional opportunities to address many significant hypotheses that cannot be adequately investigated in other existing cohorts.
 
 
 
Tennessee Colorectal Polyp Study 
PI: Zheng, WeiReid Ness         Funding Agency: NCI          Grant No.: P50 CA90949 
Description:  This project was conducted as part of the Vanderbilt SPORE in GI Cancer (PI, Robert Coffey). Recruitment for this study ended in 2010; however, data and biological samples collected in this study continue to be used in multiple studies. The primary aim of this study is to evaluate lifestyle factors and biomarkers for the risk and recurrence of colorectal polyps. Participants were recruited from patients who were scheduled for clinically-indicated colonoscopy at the VU Hospital and the VA Tennessee Valley Healthcare System. More than 7,000 patients were recruited and completed a telephone interview. Biological samples, including blood, exfoliated buccal cells, polyp tissues, and rectal biopsies, were collected from eligible subjects. The resources from this project have supported multiple externally-funded studies, including three K07 grants for career development of junior investigators and multiple R01-funded studies.
 
Tumor Markers and Recurrent Adenomas: A Follow-up Study 
PI: Zheng, Wei        Funding Agency: NCI            Grant No.: R01 CA97386 
Description: This study officially ended in 2008, but the resources it established continue to be used to support other studies. The aim of this study was to study biomarkers that can be used to predict adenoma recurrence after initial polypectomy. Approximately 1,200 patients with either an advanced adenoma or multiple adenomas were recruited from Tennessee and Indiana. Polyp tissue samples from these patients have been used to evaluate multiple tumor markers.
 
Understanding the genetic risk underlying racial disparities in uterine fibroids 
PI: Velez Edwards, Digna R         Funding Agency: NCI            Grant No. R01 HD074711 
Description: 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.
 
 
Unraveling genetic determinants of lung cancer risk in African Americans 
PI: Aldrich, Melinda      Funding Agency:  NCI       Grant No.: K07 CA172294 
Description : African Americans have the greatest risk of lung cancer compared to all other racial/ethnic groups, yet have been historically underrepresented in research. This study seeks to identify genetic factors contributing to lung cancer in African Americans and ultimately reduce their disease occurrence. This investigation into the genetics and environmental risk factors related to lung cancer will both further the field of lung cancer and also provide a strong training opportunity for the candidate to have a successful career in the broader field of genetics and cancer.
 
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Vanderbilt-Emory-Cornell-Duke Consortium for Global Health Fellows (VECDor) 
PI: Vermund, StenHeimburger, Douglas    Funding Agency:  FIC     Grant No.: R25 TW009337 
Description: This project aims to nurture a new generation of global health researchers through a collaborative training program with overseas research institutions from low and middle-income countries with which our universities have worked for decades.
 
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Vanderbilt Training Program in Molecular and Genetic Epidemiology of Cancer (MAGEC) 
PI: Shu, Xiao OuHeimburger, Douglas     Funding Agency: NCI       Grant No.: R25 CA160056 
Description: This program is designed to address the urgent need to build an elite class of epidemiologists to lead the new era of multidisciplinary collaborative research in cancer by delivering individualized didactic and research training to equip postdoctoral fellows from a variety of disciplines with the methodological tools, practical laboratory and survey-research knowledge, and hands-on research and grant writing experience necessary to launch independent careers in the molecular and genetic epidemiology of cancer.