Validation and Confirmation of Associations

Cancer is a complex phenotype resulting from the interaction of inherited and environ-mental factors. Many studies have sought to unravel this complexity by investigating onegene at a time or by considering pairwise gene-gene and gene-environment interactions.These studies have not proven as successful as hoped and led to a growing appreciation thata more comprehensive strategy is required (1). This broader strategy centers on the conceptof the biochemical pathway, which has been defined as "the sequence of reactionsundergone by a compound or class of compounds in a living organism" (2). A reaction is "achemical change, where the transformation of one or more components into new substancesoccurs, accompanied by energy changes." Some biochemical pathways are linear,proceeding in a step-by-step fashion from one molecule to another. Other pathways arebranching, generating two or more products. Pathways can also have feedback loops, forexample, when the product of a pathway controls the rate of its own synthesis throughinhibition of an early step. Each pathway is organized by the links in its chemical reactions,with the product of one reaction providing a substrate for an enzyme that catalyzes asubsequent reaction (3,4). It is evident that a pathwaywide perspective provides a broaderconceptual and analytical strategy for the detection of potential disease associations. Onecan expect the analysis of genetic variation across entire biological pathways to be morelikely to reveal the association of candidate genes with cancer risk than studies limited tosingle genes.