Presentation Information
[OE1-5]The impact of common germline risk on somatic alterations and clinical features across cancers
○Shinichi Namba1, Yuki Saito2,3, Yasunori Kogure2, Tatsuo Masuda1,4,5, Yukinori Okada1,6,7,8, Keisuke Kataoka2,9 (1.Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan, 2.Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan, 3.Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan, 4.Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan, 5.StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan, 6.Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan, 7.Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan, 8.Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan, 9.Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan)
Aggregation of genome-wide common risk variants, such as polygenic risk score (PRS), can explain genetic liability to cancer. However, it remains unknown how common germline variants associate with somatic alterations and clinical features. We constructed PRSs from 14 GWASs (median n = 64,905) for 12 cancer types using multiple methods and calibrated them using the UK Biobank resources (n = 335,048). Meta-analyses across cancer types in The Cancer Genome Atlas (TCGA) (n = 2,921) revealed that higher PRS was associated with earlier cancer onset (P = 0.001) and a lower burden of somatic alterations, including total mutations, chromosome/arm somatic copy number alterations (SCNAs), and focal SCNAs (P = 0.032, 0.008, and 0.040, respectively). As increased genomic instability is characteristic of later stages of carcinogenesis, these results suggest that common germline risk enables early tumor development before many mutations and SCNAs accumulate. The associations between PRS and somatic alterations showed no apparent heterogeneity across cancer types, in contrast to rare germline pathogenic variants associated with somatic alterations in cancer type-specific manners. We validated the associations between PRS and somatic alterations to that from TCGA using independent three prostate cancer cohorts (n = 32, 40, and 116). Our work provides the best available evidence that the overall effects of PRS on somatic alterations were maintained across cancers, different from rare pathogenic variants.