PO-303 Germline determinants of the somatic mutation landscape in 2642 cancer genomes

Introduction Cancers develop through somatic mutations; however, germline genetic variation contributes to cancer risk via diverse mechanisms including by modulating mutational processes. Material and methods Within the Pan Cancer Analysis of Whole Genomes (PCAWG) project, we discovered and phased 88 million single nucleotide variants, short insertions/deletions, and large structural variants in whole genomes from 2642 cancer patients, and employed this resource to investigate germline determinants of somatic mutation across 39 cancer types. Results and discussions We describe over 100 germline L1 retrotransposons mediating somatic retrotransposition activity in cancer. Furthermore, rare damaging germline mutations in genes involved in DNA repair, DNA replication, and cell cycle associate with a variety of somatic mutation processes. We implicate mutations in the DNA glycosylase MBD4 with an elevated rate of C>T mutations at CpG dinucleotides, resulting in the genetic modulation of a widespread mutational process. Genome-wide association analysis reveals common genetic variation within the APOBEC3 gene cluster modulating mutations attributed to APOBEC cytidine deaminases in multiple cancer types. Analysis of somatic structural variation additionally exposed complex rearrangement patterns including duplications and template insertion cycles in BRCA1-deficient cancers. Conclusion Our study underscores the notable impact rare and common germline variants have on cancer mutational landscapes.