期刊
CANCER RESEARCH
卷 83, 期 1, 页码 20-27出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-22-1492
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资金
- JSPS KAKENHI [22K20808, 22H00476]
- Australian National Health and Medical Research Council Fellowships/Investigator grants
- AMED [JP21gm4010006, JP22km0405211, JP22ek0410075, JP22km0405217, JP22ek0109594, JP21cm0106575, JP22ama221510]
- JST Moonshot RD [JPMJMS2021, JPMJMS2024, JPMJMS2022]
- Takeda Science Foundation
- Bioinformatics Initiative of Osaka University Graduate School of Medicine, Osaka University
- Uehara Memorial Foundation
- Keio University Academic Development Funds
Aggregation of genome-wide common risk variants can measure genetic susceptibility to cancer. Our results suggest that common germline cancer risk variants are associated with earlier cancer onset and lower burden of somatic alterations.
Aggregation of genome-wide common risk variants, such as polygenic risk score (PRS), can measure genetic susceptibility to cancer. A better understanding of how common germline variants associate with somatic alterations and clinical features could facilitate personalized cancer prevention and early detection. We constructed PRSs from 14 genome- wide association studies (median n = 64,905) for 12 cancer types by multiple methods and calibrated them using the UK Biobank resources (n = 335,048). Meta-analyses across cancer types in The Cancer Genome Atlas ( n = 7,965) revealed that higher PRS values were associated with earlier cancer onset and lower burden of somatic alterations, including total mutations, chromosome/arm somatic copy-number alterations (SCNA), and focal SCNAs. This contrasts with rare germline pathogenic variants (e.g., BRCA1/2 variants), showing heterogeneous associations with somatic alterations. Our results suggest that common germline cancer risk variants allow early tumor development before the accumulation of many somatic alterations characteristic of later stages of carcinogenesis.
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