Metabolic susceptibility genes as cancer risk factors: time for a reassessment?

Polymorphisms in metabolic cancer susceptibility genes have not shown a consistent role as cancer risk factors, when only main effects are examined. This is actually to be expected given the limited and specific biochemical role such genes play in the carcinogenic process. However, when particular groups of case populations are examined separately, the importance of these genetic polymorphisms may often become quite clear. Examples from the literature and a hypothetical model are presented to support the view that metabolic gene risk alleles should be studied in subgroups of large case control studies with sound biochemical hypotheses related to the action of the gene product as a function of demographic, environmental, or other genetic variables.