An immunogenetic basis for lung cancer risk-Reference-Cited by-同舟云学术

An immunogenetic basis for lung cancer risk

Published:2024-02-23 Issue:6685 Volume:383 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Krishna Chirag¹,Tervi Anniina²,Saffern Miriam³⁴,Wilson Eric A.³⁴⁵,Yoo Seong-Keun³⁴⁵,Mars Nina²,Roudko Vladimir³⁴,Cho Byuri Angela³⁴⁵,Jones Samuel Edward²,Vaninov Natalie³⁴,Selvan Myvizhi Esai⁶,Gümüş Zeynep H⁶⁷, ,Lenz Tobias L.⁸,Merad Miriam³⁴⁹¹⁰¹¹,Boffetta Paolo¹²¹³,Martínez-Jiménez Francisco¹⁴¹⁵,Ollila Hanna M.¹²¹⁶¹⁷,Samstein Robert M.³⁴⁷¹⁸,Chowell Diego³⁴⁵⁹

Affiliation:

1. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

2. Institute for Molecular Medicine, Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland.

3. The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

4. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

5. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

7. Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

8. Research Unit for Evolutionary Immunogenomics, Department of Biology, Universität Hamburg, 20146 Hamburg, Germany.

9. Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

10. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

11. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

12. Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy.

13. Stony Brook Cancer Center, Stony Brook University, New York, NY 11794, USA.

14. Vall d’Hebron Institute of Oncology, Barcelona 08035, Spain.

15. Hartwig Medical Foundation, Amsterdam 1098 XH, the Netherlands.

16. Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

17. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

18. Department of Radiation Oncology, Mount Sinai Hospital, New York, NY 10029, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adi3808

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