ABSTRACT
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 one
gene 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 that
a more comprehensive strategy is required (1). This broader strategy centers on the concept
of the biochemical pathway, which has been defined as “the sequence of reactions
undergone by a compound or class of compounds in a living organism” (2). A reaction is “a
chemical change, where the transformation of one or more components into new substances
occurs, accompanied by energy changes.” Some biochemical pathways are linear,
proceeding in a step-by-step fashion from one molecule to another. Other pathways are
branching, generating two or more products. Pathways can also have feedback loops, for
example, when the product of a pathway controls the rate of its own synthesis through
inhibition 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 a
subsequent reaction (3,4). It is evident that a pathwaywide perspective provides a broader
conceptual and analytical strategy for the detection of potential disease associations. One
can expect the analysis of genetic variation across entire biological pathways to be more
likely to reveal the association of candidate genes with cancer risk than studies limited to
single genes.
