An immunogenetic basis for lung cancer risk.

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE

Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-

Histocompatibility Antigens Class II*/genetics ; Lung Neoplasms*/genetics ; Lung Neoplasms*/immunology ; Loss of Heterozygosity* ; Immunologic Surveillance*/genetics ; Genetic Predisposition to Disease*; Humans ; Macrophages, Alveolar/immunology ; Risk Factors ; Smoking/immunology ; Middle Aged ; Aged ; Aged, 80 and over ; Chromosome Mapping ; Polymorphism, Single Nucleotide

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.

R33 CA263705 United States CA NCI NIH HHS

0 (Histocompatibility Antigens Class II)

Date Created: 20240222 Date Completed: 20240226 Latest Revision: 20241015

20250114

10.1126/science.adi3808

38386728