Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer

Abstract

Genome-wide association studies (GWAS) using population-based designs have identified many genetic loci associated with risk of a range of complex diseases including cancer; however, each locus exerts a very small effect and most heritability remains unexplained. Family-based pedigree studies have also suggested tentative loci linked to increased cancer risk, often characterized by pedigree-specificity. However, comparison between the results of population- and family-based studies shows little concordance. Explanations for this unidentified genetic 'dark matter' of cancer include phenotype ascertainment issues, limited power, gene-gene and gene-environment interactions, population heterogeneity, parent-of-origin-specific effects, and rare and unexplored variants. Many of these reasons converge towards the concept of genetic heterogeneity that might implicate hundreds of genetic variants in regulating cancer risk. Dissecting the dark matter is a challenging task. Further insights can be gained from both population association and pedigree studies.

Figure 1

Chromosomal mapping of loci present in the NHGRI catalog and identified by GWAS in (a) breast or (b) colorectal cancers. Each arrow indicates the physical mapping position of a single locus. Each GWAS is associated with a different color as follows: (A) blue [11], red [13], pink [14], green [12], orange [15], violet [16], black [17]; (B) black [75], red [25], blue [26], pink [27], green [28], violet [29].

Figure 2

Proposed role of genetic heterogeneity in individual predisposition to cancer. Colorectal cancer is given as an example. Several causative mutations at single genes (monogenic syndromes, in green), as well as variations at several loci (polygenic control) detected by either pedigree analysis (in yellow) or GWAS (in red), increase the risk of cancer. Only the 11q23.1 locus was common to pedigree and GWA studies. Either the single genetic defects or the polygenic conditions produce a cancer-prone condition in the normal tissue; individual risk of cancer might be further modulated by environmental factors, leading to somatic mutations and, ultimately, to cancer.