The transition from discovery by genome-wide association studies to validation of clinical risk models: Where are we, what will it take, and when can we expect to be there?

Abstract

Abstract Genome-wide association studies (GWAS) have emerged as an important tool for discovering regions of the genome that harbor genetic variants that confer risk for different types of cancers. The success of GWAS has been a consequence of the convergence of new technologies that can genotype hundreds of thousands of common single nucleotide polymorphism (SNP) markers together with comprehensive annotation of genetic variation. This approach has provided the opportunity to scan across the genome in a sufficiently set of cases and controls without a set of prior hypotheses in search of susceptibility alleles with low effect sizes. So far, susceptibility alleles discovered thus far are common, namely, with a frequency in one or more population of greater than 5% and each allele confers a small contribution to the overall risk for the disease. In prostate cancer, there could be more than 35 distinct regions harboring common susceptibility alleles identified by GWAS whereas in lung cancer, a disease strongly driven by exposure to tobacco products, so far, only three regions have been conclusively established. To date, over 125 regions have been conclusively associated in over a dozen different cancers, yet no more than six regions have been associated with more than one distinct cancer type. GWAS are an important discovery tool that require extensive follow-up to map each region, investigate the biological mechanism underpinning the association and eventually test the optimal markers for assessing risk for a disease or its outcome, such as in pharmacogenomics. The early fruits of success employed by GWAS have opened new horizons for applying genetic variation to the early diagnosis, treatment and perhaps prevention of different types of cancers. At the same time, it has become apparent that the complex genomic architecture of disease susceptibility will require further discovery of uncommon and rare variants using next generation sequence technologies that contribute to different cancers before we can expect to establish robust tests of germline DNA to be clinically useful. To reach this goal, new studies will need to be designed to validate the utility of known genetic variants in assessing risk for cancer.