Population Studies
The Genetic Epidemiology Branch designs and conducts highly interdisciplinary clinical, epidemiologic, genetic and laboratory studies in populations to evaluate the relevance of genetic variations in cancer etiology. We use a broad range of methodologies including case-control, cohort, family-based and molecular epidemiology designs. We also develop new methodologies to address specific design and analytic issues. Examples of selected studies are listed below.
Studies in Data Accrual
Studies in Data Accrual
Risk Factors for Breast Cancer Classified According to Expression of Hormonal Markers
To improve the risk classification characterized by molecular markers, large population-based epidemiologic studies with strong pathology components are needed. A large population-based breast cancer case-control study conducted in Poland, including 2,386 incident cases and 2,502 randomly selected controls, provides an ideal resource. In collaboration with the Hormonal and Reproductive Epidemiology Branch, DCEG, we have constructed tissue microarrays (TMAs) of invasive breast tumors and non-invasive tissues (ductal carcinoma in situ and normal terminal ductal lobular units) collected for the Polish study, and stained these TMAs for molecular markers. The goals of this study include:
- To identify etiologically heterogeneous subsets of breast tumors by examining the expression and co-expression patterns of molecular markers involved in important pathways for breast carcinogenesis.
- To compare marker expression in invasive tumors and non-invasive tissues for a better understanding of molecular mechanisms involved in tumor progression.
- To identify new markers for novel molecular classification of breast tumors into etiologically distinct subtypes using an integrated approach of tumor profiling (mRNA expression, gene copy number, microRNA, and methylation changes).
Genetic and Molecular Epidemiology Studies of Melanoma in Italy
A case-control study is being conducted in Italy to study the role of pigmentation and other host factors in the etiology of melanoma in a population with a wide range of pigmentary phenotypes and intense sun exposure. This is a collaborative study between the NCI, Bufalini Hospital, Cesena, and the University of L’Aquila, L’Aquila, Italy. The study includes over 350 melanoma cases and 350 healthy controls, matched by age, sex and residence. To address the genetic determinants of melanoma in the Mediterranean population through a different approach, a family study of melanoma is also currently ongoing in the same areas of Italy. To date, the study includes 76 families with 2 to 5 melanoma-affected individuals per family. Unaffected relatives from these families are also enrolled.
An additional project includes melanoma patients participating in either the Italian case/control or the Italian family study of melanoma who have agreed to donate multiple tissue biopsies from normal skin, common melanocytic nevi, dysplastic nevi and melanoma to allow the investigation of the pathways potentially involved in the transition from common nevi to melanoma.
Screening for CPG Methylation and Allele Loss on Chromosome 14q to Identify Candidate Tumor Suppressor Genes in Nasopharyngeal Carcinoma
The goal of this study is to follow-up on chromosomal regions identified from a genome-wide linkage analysis of nasopharyngeal carcinoma (NPC) families in Taiwan and an independent gene expression analysis of sporadic NPC tumors collected from a case-control study also conducted in Taiwan. We will use an integrated genetic and epigenetic approach to identify genes that are important for the development of NPC. The specific objectives include:
- To identify mechanisms associated with altered gene expression in NPC tumors at chromosomal regions identified by linkage and expression profiling by screening NPC tumors for promoter methylation and copy number changes.
- To narrow the region and/or number of genes on those regions potentially involved in NPC development.
Barrett’s Esophagus Early Detection Study
The Barrett’s Esophagus Early Detection Study was initiated in July 2006, with the primary goal of identifying a practical blood-based biomarker to distinguish persons with Barrett’s esophagus (BE) from those without it. This BE case-control study is being conducted at the National Naval Medical Center in Bethesda, Maryland, among Barrett’s Esophagus Registry patients and non-BE patients who have endoscopies in the Gastroenterology Clinic.
Cancer Genetic Studies in Shanxi Province, China
The Upper Gastrointestinal Cancer Genetic Studies in Shanxi Province, China, were started in 1995 to look for major susceptibility genes for upper gastrointestinal (UGI) cancers and to identify the genetic changes associated with their development. This project was initiated to study esophageal squamous cell carcinomas, but also includes other UGI cancers (gastric cardia cancer and gastric non-cardia cancer). The project goals include:
- Studies of somatic genetic alterations in tumors;
- Evaluation of somatic molecular markers in pre-malignant tissues in our search for early detection markers; and
- Examination of cancer-associated germ-line genetic variants to identify major risk and moderate risk susceptibility genes to enable development of risk stratification strategies and a better understanding of the biology of these UGI cancers.
Nutrition Intervention Trials in Linxian, China
The original goal of the Nutrition Intervention Trials (NIT) was to evaluate the role of nutrition in the etiology and prevention of upper gastrointestinal cancers in over 32,000 residents in Linxian, China. With the conclusion of the intervention phase in 1991, and the determination that the micronutrient combination of selenium/vitamin E/ß-carotene reduced total mortality, total cancer mortality, and gastric cancer mortality, objectives now include:
- Determination of post-trial effects of the interventions;
- Evaluation of etiologic hypotheses, including nutrition, carcinogens, infections, genetics, and other exposures;
- Studies of natural history; and
- Examination of interactions (gene-environment, gene-gene, and gene-intervention).
In collaboration with the Cancer Institute of the Chinese Academy of Medical Sciences in Beijing, we continue to follow trial participants to ascertain endpoints, conduct nested case-control and case-cohort studies using baseline serum, and perform expanded DNA and biochemical analyses on additional blood samples collected during follow-up.
Studies in Analysis
Brain Tumor Family Study of Genetic Susceptibility and Environmental Factors
This study was a follow-up study to a DCEG case-control study of brain tumors led by the Radiation Epidemiology Branch, DCEG. The follow-up study focused primarily on first-degree relatives of the glioma patients ascertained through the case-control study. Information was obtained about each relative’s personal and family history of cancer and other diseases, and history of risk factor exposures. The goals of the study are to examine the aggregation of cancers in families of glioma cases, to examine the risk factors associated with glioma, and to compare results from this evaluation to results from the case-control study to help identify additional genetic and environmental risk factors for glioma.
Population Studies of Hematologic Tumors using Scandinavian Registries
The ability to link population-based registries containing parent-offspring links with cancer registries and hospital discharge registries in the Scandinavian countries allows us to conduct studies of familial aggregation of cancers. In alliance with collaborators in Sweden and Denmark, we conduct investigations designed to quantify familial aggregation of hematologic cancers and related conditions. The overall goals of these studies are to assess:
- Familial aggregation of lymphoproliferative and myeloproliferative hematologic malignancies and related precursor conditions.
- Family and personal history of immune-related and inflammatory disorders and risk of hematologic neoplasms.
- Disease characteristics and outcomes for familial hematologic malignancies and related precursor conditions.
Environment And Genes in Lung cancer Etiology (EAGLE)
EAGLE is a large population-based case-control study designed and conducted to investigate the genetic and environmental determinants of lung cancer and smoking persistence using an integrative approach that allows combined analysis of genetic, environmental, clinical, and behavioral data. The study includes over 2,000 incident lung cancer cases, both males and females of Italian nationality, ages 35 to 79 years old, with verified lung cancer of any histological type, and over 2,000 healthy population-based controls matched to cases by age, gender, and residence.
Over 500,000 single nucleotide polymorphisms (SNPs) will be genotyped to identify genetic susceptibility to lung cancer risk and survival, and to smoking persistence in this project which was awarded funding by the National Human Genome Research Institute Genes, Environment and Health Initiative (GEI). After validation of a proportion of the significant SNPs in collaborative replication studies, further steps will include fine mapping of verified regions of interest, gene resequencing, and functional assays to provide biological clues for the findings. Analyses of smoking and other phenotypes across GEI-funded genome-wide association studies (GWAS) are planned.
Investigations of Genomic and Somatic DNA in Renal Cancer Susceptibility Genes in the Central European Renal Cancer Case-Control Study
A large hospital-based case-control study of renal cancer carcinoma (RCC) led by the Occupational and Environmental Epidemiology Branch, DCEG, was conducted in Central and Eastern Europe from 1999 to 2003. This study was a collaboration between the NCI and the International Agency for Research on Cancer (IARC). The study included 925 cases of RCC and 1247 controls matched on age, gender, and study centers in Russia, Romania, Poland, and Czech Republic. The VHL-HIF (von Hippel Lindau-Hypoxia Inducible Factor) pathway has been implicated in the etiology of cancer, especially RCC. To date, the role of common genetic variants in genes in the VHL-HIF pathway has not been investigated in the susceptibility of kidney cancer in a large population. The objective of this project is to investigate whether single nucleotide polymorphisms (SNPs) or haplotypes in genes of the VHL-HIF pathway are associated with the susceptibility to kidney cancer in the general population.
