COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration

Linkage analysis, positional cloning, candidate gene muta tion scanning and genome-wide association study approaches have all contributed signifi cantly to our understanding of the underlying genetic architecture of breast cancer. Taken together, these approaches have identifi ed genetic variation that explains approximately 30% of the overall familial risk of breast cancer, implying that more, and likely rarer, genetic susceptibility alleles remain to be discovered. Th e application of massively parallel sequencing has further demonstrated the complexity of human genetic variation and has raised many challenges for computational and statistical methods for searching for additional breast cancer predisposition genes. Early fi ndings are consistent with previous indications that no single gene is likely to account for a large proportion of the remaining unexplained genetic susceptibility [1,2]. Coordinated international collaboration off ers great potential to advance the discovery of additional breast cancer susceptibility genes by increasing the likelihood of identifying functionally relevant genetic variants in the same genes in multiple families. A new consortium, COMPLEXO (a name chosen to refl ect the complexity of the exome), has been formed to facilitate collaborations between researchers actively applying massively parallel sequencing to understand the genetics of breast and ovarian cancer. Th e consortium has defi ned activities aimed at bringing together data and resources suitable for exome/genome sequencing initiatives and for large case-control-family study resources suitable for validation of candidate susceptibility genes in which rare mutations are associated with high to moderate risk of breast cancer. Th e aim of COMPLEXO is to bring to massively