Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans.

Boffetta P, Winn DM, Ioannidis JP, Thomas DC, Little J, Davey Smith G, Cogliano VJ, Hecht SS, Seminara D, Vineis P, Khoury MJ.

Source

Tisch Cancer Institute, Mount Sinai School of Medicine, New York, USA, International Prevention Research Institute, Lyon, France, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, Stanford Prevention Research Center, Department of Medicine and Department of Health Research and Policy, Stanford University School of Medicine, Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, CA, USA, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece, Center for Genetic Epidemiology and Modeling, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA, Biostatistics Division, Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA, Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada, Department of Social Medicine, University of Bristol, Bristol, UK, International Agency for Research on Cancer, Lyon, France, Masonic Cancer Center, University of Minnesota Minneapolis, MN, USA, MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College, London, UK, HuGeF Foundation, Turin, Italy and Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA, USA.

Abstract

We propose guidelines to evaluate the cumulative evidence of gene-environment (G × E) interactions in the causation of human cancer. Our approach has its roots in the HuGENet and IARC Monographs evaluation processes for genetic and environmental risk factors, respectively, and can be applied to common chronic diseases other than cancer. We first review issues of definitions of G × E interactions, discovery and modelling methods for G × E interactions, and issues in systematic reviews of evidence for G × E interactions, since these form the foundation for appraising the credibility of evidence in this contentious field. We then propose guidelines that include four steps: (i) score the strength of the evidence for main effects of the (a) environmental exposure and (b) genetic variant; (ii) establish a prior score category and decide on the pattern of interaction to be expected; (iii) score the strength of the evidence for interaction between the environmental exposure and the genetic variant; and (iv) examine the overall plausibility of interaction by combining the prior score and the strength of the evidence and interpret results. We finally apply the scheme to the interaction between NAT2 polymorphism and tobacco smoking in determining bladder cancer risk.