An immunogenetic basis for lung cancer risk
成果类型：
Article
署名作者：
Krishna, Chirag; Tervi, Anniina; Saffern, Miriam; Wilson, Eric A.; Yoo, Seong-Keun; Mars, Nina; Roudko, Vladimir; Cho, Byuri Angela; Jones, Samuel Edward; Vaninov, Natalie; Selvan, Myvizhi Esai; Gumus, Zeynep H.; Lenz, Tobias L.; Merad, Miriam; Boffetta, Paolo; Martinez-Jimenez, Francisco; Ollila, Hanna M.; Samstein, Robert M.; Chowell, Diego
署名单位：
Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Helsinki; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; University of Hamburg; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; University of Bologna; State University of New York (SUNY) System; Stony Brook University; Vall d'Hebron Institut d'Oncologia (VHIO); Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Icahn School of Medicine at Mount Sinai
刊物名称：
SCIENCE
ISSN/ISSBN：
0036-13474
DOI：
10.1126/science.adi3808
发表日期：
2024-02-23
关键词：
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.