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 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 10th–011th, 2012. The objective of the Think Tank was to facilitate discussions on: 1) the state of the science; 2) the goals of gene-environment 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 gene-environment 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.

Interferon Regulatory Factor 6 (IRF6) and Gene – Environment Interactions in Non-Syndromic Orofacial Cleft Cases in Saudi Arabia-A Case Control Study

“…This significant association concurs with a population based case-control study in Northern Netherlands that reported "duration of exposure-response effect" increased the risk of cleft lip [30].…”

“…However, achieving this number is difficult, particularly because NSOFC is a rare disease and sub-phenotyping is necessary. In addition, there are multiple risk factors that contribute to these diseases [9,30].…”

Genetic Control of Environmental Variation of Two Quantitative Traits ofDrosophila melanogasterRevealed by Whole-Genome Sequencing

“…The literature on the subject can be distinguished between attempts at documenting the existence of genetic factors influencing variation and those aimed at finding the specific genes involved. The latter are more recent and involve fewer studies (Ansel et al 2008;Jimenez-Gomez et al 2011;Shen et al 2012;Hutter et al 2013) and the focus in some is on analysis of the marginal phenotypic variation (Yang et al 2012a). This is different from the subject of the present study, where the focus is on the conditional variance, given the genotype.…”

“…The first definition gives rise to genotype-byenvironment interaction at the level of the mean, a topic that has a long history due to its relevance in livestock and plant breeding as well as in medical genetics. Recent articles on specific areas are Huquet et al (2012) in livestock, El-Soda et al (2014) in plants, andHutter et al (2013) in humans.The second definition implies that environmental variance is under genetic control and is the subject of the present work. Genetic control of environmental variation has implications in evolutionary biology, in animal and plant improvement, and in medicine.…”

“…The first definition gives rise to genotype-byenvironment interaction at the level of the mean, a topic that has a long history due to its relevance in livestock and plant breeding as well as in medical genetics. Recent articles on specific areas are Huquet et al (2012) in livestock, El-Soda et al (2014) in plants, and Hutter et al (2013) in humans.…”