Our study has important implications for the design and analysis of molecular epidemiology studies in cancer as well as the somatic characterization of cancer genomes, like The Cancer Genome Atlas32 and International Cancer Genome Consortium33. Investigators will need to carefully analyze samples used as exemplars of germline DNA for somatic alterations, such as detectable clonal mosaicism. Otherwise, comparisons between “grmline” and tumor DNA may result in implausible somatic changes (e.g. large gains of heterozygosity) and it may be impossible to determine whether somatic events pre-date changes secondary to driver mutations. Since how to detect mosaic events with next generation sequencing technologies is neither routine nor well understood, for the near future it may be prudent to continue to utilize SNP microarrays for such analyses. Due to the increased frequency of detectable clonal mosaicism with age, this will be particularly important for the analysis of epithelial cancers, which characteristically occur in the older population. For future large-scale GWAS in prospective studies, it may be wise to consider analyzing the earliest, pre-diagnosis DNA samples and to consider time from collection to diagnosis in the analysis of longitudinally collected biospecimens.
