An immunogenetic basis for lung cancer risk

Chirag Krishna, Anniina Tervi, Miriam Saffern, Eric A. Wilson, Seong Keun Yoo, Nina Mars, Vladimir Roudko, Byuri Angela Cho, Samuel Edward Jones, Natalie Vaninov, Myvizhi Esai Selvan, Zeynep H. Gümüş, FinnGen, Tobias L. Lenz, Miriam Merad, Paolo Boffetta, Francisco Martínez-Jiménez, Hanna M. Ollila, Robert M. Samstein, Diego Chowell

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish
Article numbereadi3808
Pages (from-to)1-18
Number of pages18
Issue number6685
StatePublished - 23 Feb 2024


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