Gene-Environment Interactions in Cancer Epidemiology: A National Cancer Institute Think Tank Report
ABSTRACT Cancer risk is determined by a complex interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified hundreds of common (minor allele frequency [MAF] > 0.05) and less common (0.01 < MAF < 0.05) genetic variants associated with cancer. The marginal effects of most of these variants have been small (odds ratios: 1.1-1.4). There remain unanswered questions on how best to incorporate the joint effects of genes and environment, including gene-environment (G × E) interactions, into epidemiologic studies of cancer. To help address these questions, and to better inform research priorities and allocation of resources, the National Cancer Institute sponsored a "Gene-Environment Think Tank" on January 10-11, 2012. The objective of the Think Tank was to facilitate discussions on (1) the state of the science, (2) the goals of G × E interaction studies in cancer epidemiology, and (3) opportunities for developing novel study designs and analysis tools. This report summarizes the Think Tank discussion, with a focus on contemporary approaches to the analysis of G × E interactions. Selecting the appropriate methods requires first identifying the relevant scientific question and rationale, with an important distinction made between analyses aiming to characterize the joint effects of putative or established genetic and environmental factors and analyses aiming to discover novel risk factors or novel interaction effects. Other discussion items include measurement error, statistical power, significance, and replication. Additional designs, exposure assessments, and analytical approaches need to be considered as we move from the current small number of success stories to a fuller understanding of the interplay of genetic and environmental factors.
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ABSTRACT: Most complex human diseases are likely the consequence of the joint actions of genetic and environmental factors. Identification of gene-environment (G × E) interactions not only contributes to a better understanding of the disease mechanisms, but also improves disease risk prediction and targeted intervention. In contrast to the large number of genetic susceptibility loci discovered by genome-wide association studies, there have been very few successes in identifying G × E interactions, which may be partly due to limited statistical power and inaccurately measured exposures. Although existing statistical methods only consider interactions between genes and static environmental exposures, many environmental/lifestyle factors, such as air pollution and diet, change over time, and cannot be accurately captured at one measurement time point or by simply categorizing into static exposure categories. There is a dearth of statistical methods for detecting gene by time-varying environmental exposure interactions. Here, we propose a powerful functional logistic regression (FLR) approach to model the time-varying effect of longitudinal environmental exposure and its interaction with genetic factors on disease risk. Capitalizing on the powerful functional data analysis framework, our proposed FLR model is capable of accommodating longitudinal exposures measured at irregular time points and contaminated by measurement errors, commonly encountered in observational studies. We use extensive simulations to show that the proposed method can control the Type I error and is more powerful than alternative ad hoc methods. We demonstrate the utility of this new method using data from a case-control study of pancreatic cancer to identify the windows of vulnerability of lifetime body mass index on the risk of pancreatic cancer as well as genes that may modify this association.Genetic Epidemiology 11/2014; 38(7). DOI:10.1002/gepi.21852 · 2.95 Impact Factor
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ABSTRACT: We studied the interplay between 39 breast cancer (BC) risk SNPs and established BC risk (body mass index, height, age at menarche, parity, age at menopause, smoking, alcohol and family history of BC) and prognostic factors (TNM stage, tumor grade, tumor size, age at diagnosis, estrogen receptor status and progesterone receptor status) as joint determinants of BC risk. We used a nested case-control design within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), with 16 285 BC cases and 19 376 controls. We performed stratified analyses for both the risk and prognostic factors, testing for heterogeneity for the risk factors, and case-case comparisons for differential associations of polymorphisms by subgroups of the prognostic factors. We analyzed multiplicative interactions between the SNPs and the risk factors. Finally, we also performed a meta-analysis of the interaction ORs from BPC3 and the Breast Cancer Association Consortium. After correction for multiple testing, no significant interaction between the SNPs and the established risk factors in the BPC3 study was found. The meta-analysis showed a suggestive interaction between smoking status and SLC4A7-rs4973768 (Pinteraction = 8.84 × 10(-4)) which, although not significant after considering multiple comparison, has a plausible biological explanation. In conclusion, in this study of up to almost 79 000 women we can conclusively exclude any novel major interactions between genome-wide association studies hits and the epidemiologic risk factors taken into consideration, but we propose a suggestive interaction between smoking status and SLC4A7-rs4973768 that if further replicated could help our understanding in the etiology of BC.Human Molecular Genetics 05/2014; DOI:10.1093/hmg/ddu223 · 6.68 Impact Factor
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ABSTRACT: To assess the effect of the NFKB1 -94ins/del polymorphism on cancer, we conducted a meta-analysis based on 25 studies including 8,750 cases and 9,170 controls. Overall, the -94ins/del polymorphism was associated with cancer risk in the pooled analysis and in Asian population, whereas no association was observed in Caucasian population. Stratified analysis by subtypes of cancer showed that the -94ins/del polymorphism was associated with oral squamous cell carcinoma and ovarian cancer risk, but had no association with colorectal cancer, bladder cancer, and renal cell cancer. Our meta-analysis suggests the NFKB1 -94ins/del polymorphism affects cancer susceptibility, and the association is ethnic-specific.Cancer Investigation 05/2014; DOI:10.3109/07357907.2014.911881 · 2.06 Impact Factor