Etiologic impact of known cancer susceptibility genes

The impact of a gene variant on the population burden of cancer can be measured by the population attributable fraction (PAF), which depends on the risk conferred by the variant, genotype relative risk (GRR), the frequency of the variant in the population and the mode of inheritance. PAF defines the proportion of the disease in the study population due to a gene variant, hence the synonymic term, etiologic fraction. After a review of the literature, 27 confirmed cancer susceptibility genes, groups of genes and loci were selected for analysis on the basis of their prevalence and availability of validated GRR data. The covered variants represent the most common established cancer susceptibility genes; those not included have marginal PAFs on common cancers. The PAF due to known genes at the covered sites was highest for brain hemangioblastoma (19%), conferred by the VHL gene. For colorectal cancer, the PAF estimates amounted to 7.0%. Including genes and identified loci from whole genome scans, PAFs for both breast and prostate cancers summed up to 70%. The derived estimates should rectify common overstatements on the contribution of individual high penetrance genes on common cancers at the population level. More dramatically, the estimates show the large PAFs conferred by the recently discovered breast, prostate and colorectal cancer loci, most of which are not known to alter coding sequences or expression patterns and they thus act through yet unexplained mechanisms. Although of low risk, these common variants appear to explain large proportions of breast and prostate cancers in the population.