肺癌
基础(线性代数)
医学
风险分析(工程)
计算生物学
生物
肿瘤科
数学
几何学
作者
Chirag Krishna,Anniina Tervi,Miriam Saffern,E. A. Wilson,Seong-Keun Yoo,Nina Mars,Vladimir Roudko,Byuri Angela Cho,Samuel E. Jones,Natalie Vaninov,Myvizhi Esai Selvan,Zeynep H. Gümüş,Tobias Lenz,Miriam Mérad,Paolo Boffetta,Francisco Martínez-Jiménez,Hanna Ollila,Robert M. Samstein,Diego Chowell
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2024-02-23
卷期号:383 (6685)
标识
DOI:10.1126/science.adi3808
摘要
Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA) -II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA -II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA -II+ epithelial cells. In lung cancer, widespread loss of HLA -II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.
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