Introduction

Until relatively recently the field of medical genetics has focused on the identification and treatment of rare, single-gene disorders that are usually associated with a high risk of a particular disease or trait. However, such high-penetrance susceptibility loci only account for a fraction of the familial aggregation of common diseases, and the genetic architecture of complex diseases, such as cancer, is probably better characterized by “polygenic” inheritance, wherein heritability is determined by the joint action of multiple genes. Since 2007, genome-wide association studies (GWAS) have resulted in a paradigm shift in the discovery of gene–disease associations and helped to identify multiple low-penetrance germline genetic variants for most common cancer types (1,2). Through a hypothesis-neutral genome-based approach, GWAS compare frequencies of common DNA variations, usually in the form of single-nucleotide polymorphisms (SNPs), in a large set of unrelated cases and controls to identify genetic variants associated with disease risk. GWAS have resulted in the mapping of susceptibility loci for many human diseases, including the identification of over 100 loci for cancer, most of which were not previously implicated in carcinogenesis.

This unprecedented rapid amassing of new genetic risk variants associated with cancer risk has generated hope that these germline markers may prove useful for cancer prevention, improve our understanding of cancer pathogenesis, and possibly lead to a new era of personalized genomics (3). However, as the majority of genetic variants confer only a modest risk of disease with effect size under 1.5 (Figure 2.1) and the biological mechanisms underpinning most associations are unknown, significant scientific barriers must be overcome before GWAS results can be meaningfully translated into patient care.