Genetic Heterogeneity and Cancer
The following paper raises the important issue of genetic heterogeneity. This is a nice paper because it addresses the complexity of genetic architecture. However, it is very poorly cited. Note how few citations there are before the year 2000. This is not a new idea. It would have been nice if they could have provided the reader with a historical perspective on this important phenomenon.
Galvan A, Ioannidis JP, Dragani TA. Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer. Trends Genet. 2010 Jan 25. [Epub ahead of print] [PubMed] PMID: 20106545.
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.