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

Int J Epidemiol. 2012 June; 41(3): 686–704.

Published online 2012 May 16. doi: 10.1093/ije/dys010

PMCID: PMC3481885

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

Paolo Boffetta,^1,2,* Deborah M Winn,³ John P Ioannidis,^4,5,6,7 Duncan C Thomas,⁸ Julian Little,⁹ George Davey Smith,¹⁰ Vincent J Cogliano,¹¹ Stephen S Hecht,¹² Daniela Seminara,³ Paolo Vineis,^13,14 and Muin J Khoury¹⁵

¹Tisch Cancer Institute, Mount Sinai School of Medicine, New York, USA, ²International Prevention Research Institute, Lyon, France, ³Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, ⁴Stanford Prevention Research Center, Department of Medicine and Department of Health Research and Policy, Stanford University School of Medicine, ⁵Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, CA, USA, ⁶Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece, ⁷Center for Genetic Epidemiology and Modeling, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA, ⁸Biostatistics Division, Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA, ⁹Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada, ¹⁰Department of Social Medicine, University of Bristol, Bristol, UK, ¹¹International Agency for Research on Cancer, Lyon, France, ¹²Masonic Cancer Center, University of Minnesota Minneapolis, MN, USA, ¹³MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College, London, UK, ¹⁴HuGeF Foundation, Turin, Italy and ¹⁵Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA, USA

*Corresponding author. Institute for Translational Epidemiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1057, New York, NY 10029, USA. E-mail: paolo.boffetta@mssm.edu

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Accepted January 17, 2012.

Copyright Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved.

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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.

Keywords: Genetics, environment, interactions, evaluations