Genetic dissection of intermediate phenotypes as a way to discover novel cancer susceptibility alleles.

The availability of affordable genome-wide association (GWA) studies has led to the discovery of a large number of cancer risk alleles. The prospects of identifying additional alleles using the same disease-based approach are limited unless very large samples sizes are used in future investigations. An alternative and powerful way to identify additional cancer genes is to study intermediate phenotypes, such as variation in DNA repair capacity, that are known to be associated with increased disease risk. Most of these phenotypes are highly genetic. Their measurement can be achieved using well-established medium-throughput to high-throughput methods and their genetic mapping can be carried out with relatively small sample sizes. The genetic variants associated with these phenotypes will represent ideal functionally validated candidates for cancer susceptibility studies. Unlike hypothesis-free and disease-based GWA-discovered alleles, intermediate phenotype alleles that mediate cancer risk will have a strong biological relevance and will represent excellent modifiable or 'drugable' therapeutic targets.