講演情報
[OE1-5]生殖細胞系列の遺伝的要因ががん体細胞異常に与える影響の網羅的解明
○難波 真一1, 斎藤 優樹2,3, 木暮 泰寛2, 増田 達郎1,4,5, 岡田 随象1,6,7,8, 片岡 圭亮2,9 (1.大阪大学 大学院医学系研究科 遺伝統計学, 2.国立がん研究センター研究所 分子腫瘍学分野, 3.慶應義塾大学 医学部 内科学（消化器）, 4.大阪大学 大学院医学系研究科 産科学婦人科学, 5.大阪大学 再生誘導医学協働研究所, 6.東京大学 大学院医学系研究科 遺伝情報学, 7.理化学研究所 生命医科学研究センター システム遺伝学チーム, 8.大阪大学 免疫学フロンティア研究センター 免疫統計学, 9.慶應義塾大学 医学部 内科学（血液）)
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.