A New Frontier for Cancer Genetics: Identification of Germline-Somatic Associations

Studies of the inherited or germline genome have identified rare mutations with large effects and common polymorphisms of more modest effect sizes that are associated with cancer risk. This research has substantially illuminated the etiology and development of cancer, with particular relevance to cancer prevention. In parallel, studies of the somatic or tumor genome have been instrumental in identifying the key drivers of cancer progression, significantly informing modern cancer therapy. While these studies have thus far largely been performed separately, integrative studies where the germline and somatic genomes are mapped in the same individuals have the potential to yield novel and holistic insights into cancer biology. In this issue of Cancer Research, Liu and colleagues report the results of integrative germline-somatic analyses in over 12,000 patients with cancer and 11 cancer types, identifying several associations where inherited variants that regulate the expression of a nearby gene in normal tissues are associated with tumor mutations in the same gene or with genome-wide somatic traits such as the tumor mutational burden. Although considerable follow-up work is required, the study is an important contribution to an emerging body of evidence that is demonstrating that the germline has a vital role in shaping the tumor genome. See related article by Liu et al., p. 1191.