Gene–environment interaction and aetiology of cancer: what does it mean and how can we measure it?

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Abstract
One form of defence against cancer development involves a series of genes whose role is to metabolize and excrete potentially toxic compounds and to repair subtle mistakes in DNA. Much laboratory and epidemiological research over the past decade has concentrated on the identification of these genes and an assessment of their role in cancer aetiology. Of particular interest has been whether the risk of cancer associated with a particular environmental exposure differs with respect to functionally different polymorphisms of these genes, i.e. gene–environment interaction. A large number of studies have been conducted for numerous genes and also for all common cancer sites, although results have been very inconsistent and therefore inconclusive. This is partially due to the inadequate sample size of most studies to detect modest effects and the over-reporting of positive associations identified in subgroups of the dataset. There is also much confusion about the meaning of `gene–environment interaction', what type of studies should be conducted to study it and also how it should be measured. Furthermore, the very purpose of these studies is not clear; are they attempting to identify high-risk individuals, or are they simply trying to further understand the cancer process? This review will explore these questions and provide some recommendations to help ensure that the next phase of gene–environment interaction studies, which are likely to be much larger and based on many more genes, also provide some clearer answers.