PMID- 38386728 OWN - NLM STAT- MEDLINE DCOM- 20240226 LR - 20240227 IS - 1095-9203 (Electronic) IS - 0036-8075 (Linking) VI - 383 IP - 6685 DP - 2024 Feb 23 TI - An immunogenetic basis for lung cancer risk. PG - eadi3808 LID - 10.1126/science.adi3808 [doi] AB - 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. FAU - Krishna, Chirag AU - Krishna C AD - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. FAU - Tervi, Anniina AU - Tervi A AD - Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland. FAU - Saffern, Miriam AU - Saffern M AD - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Wilson, Eric A AU - Wilson EA AD - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Yoo, Seong-Keun AU - Yoo SK AD - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Mars, Nina AU - Mars N AD - Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland. FAU - Roudko, Vladimir AU - Roudko V AD - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Cho, Byuri Angela AU - Cho BA AD - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Jones, Samuel Edward AU - Jones SE AD - Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland. FAU - Vaninov, Natalie AU - Vaninov N AD - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Selvan, Myvizhi Esai AU - Selvan ME AD - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Gumus, Zeynep H AU - Gumus ZH AD - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. CN - FinnGen section sign FAU - Lenz, Tobias L AU - Lenz TL AD - Research Unit for Evolutionary Immunogenomics, Department of Biology, Universitat Hamburg, 20146 Hamburg, Germany. FAU - Merad, Miriam AU - Merad M AD - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Boffetta, Paolo AU - Boffetta P AD - Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy. AD - Stony Brook Cancer Center, Stony Brook University, New York, NY 11794, USA. FAU - Martinez-Jimenez, Francisco AU - Martinez-Jimenez F AD - Vall d'Hebron Institute of Oncology, Barcelona 08035, Spain. AD - Hartwig Medical Foundation, Amsterdam 1098 XH, the Netherlands. FAU - Ollila, Hanna M AU - Ollila HM AD - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. AD - Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland. AD - Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. AD - Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. FAU - Samstein, Robert M AU - Samstein RM AD - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Radiation Oncology, Mount Sinai Hospital, New York, NY 10029, USA. FAU - Chowell, Diego AU - Chowell D AD - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. AD - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. LA - eng PT - Journal Article DEP - 20240223 PL - United States TA - Science JT - Science (New York, N.Y.) JID - 0404511 RN - 0 (Histocompatibility Antigens Class II) SB - IM MH - Humans MH - *Histocompatibility Antigens Class II/genetics MH - *Lung Neoplasms/genetics/immunology MH - Macrophages, Alveolar/immunology MH - Risk Factors MH - *Loss of Heterozygosity MH - Smoking/immunology MH - *Immunologic Surveillance/genetics MH - Middle Aged MH - Aged MH - Aged, 80 and over MH - *Genetic Predisposition to Disease MH - Chromosome Mapping MH - Polymorphism, Single Nucleotide EDAT- 2024/02/22 18:43 MHDA- 2024/02/26 06:45 CRDT- 2024/02/22 14:04 PHST- 2024/02/26 06:45 [medline] PHST- 2024/02/22 18:43 [pubmed] PHST- 2024/02/22 14:04 [entrez] AID - 10.1126/science.adi3808 [doi] PST - ppublish SO - Science. 2024 Feb 23;383(6685):eadi3808. doi: 10.1126/science.adi3808. Epub 2024 Feb 23.