An immunogenetic basis for lung cancer risk

• Published in: Science (American Association for the Advancement of Science) 2024-02, Vol.383 (6685), p.eadi3808
• Main Authors: 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, Gümüş, Zeynep H, Lenz, Tobias L, Merad, Miriam, Boffetta, Paolo, Martínez-Jiménez, Francisco, Ollila, Hanna M, Samstein, Robert M, Chowell, Diego
• Format: Article
• Language: English
• Subjects: Adaptive systems; Aged; Aged, 80 and over; Amino acids; Antigen presentation; Antigenic determinants; Antigens; Biobanks; Cancer; CD4 antigen; Cell surface; Chromosome Mapping; DNA biosynthesis; Drb1 protein; Epithelial cells; Epithelium; Gene polymorphism; Gene sequencing; Genetic diversity; Genetic Predisposition to Disease; Genetics; Genomes; Genomic analysis; Grooves; Health risk assessment; Health risks; Heterozygote advantage; Histocompatibility antigen HLA; Histocompatibility Antigens Class II - genetics; Homozygosity; Humans; Immune response; Immune system; Immunogenetics; Immunologic Surveillance - genetics; Immunosurveillance; Leukocytes; Loss of Heterozygosity; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lymphocytes; Lymphocytes T; Macrophages; Macrophages, Alveolar - immunology; Major histocompatibility complex; Medical screening; Middle Aged; Mutation; Outcomes of Treatment; Peptides; Polymorphism; Polymorphism, Single Nucleotide; Risk analysis; Risk assessment; Risk Factors; Risk management; Smoking; Smoking - immunology; Tobacco; Tobacco smoking; Tumors
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adi3808

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 -II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the -II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and -II+ epithelial cells. In lung cancer, widespread loss of -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.