Germline HLA heterozygosity is associated with decreased lung cancer risk

Heterozygosity at human leukocyte antigen (HLA) loci may improve lung cancer immunosurveillance by increasing recognition of the tumor by the immune system. Previous studies utilizing data from population-level biobanks, such as the United Kingdom Biobank and FinnGen, have identified an association between germline HLA class II (HLA-II) heterozygosity and reduced lung cancer risk in smokers. In the present study, we evaluate the association between HLA heterozygosity and lung cancer in a large case-control study (15,302 cases and 14,580 controls) with imputed HLA allele-type information, comparing differences in HLA heterozygosity between smokers and non-smokers, among lung cancer subtypes, and at 2- and 4-digit HLA allele resolution. We identify a strong protective association of HLA-II heterozygosity in smokers compared to non-smokers, particularly at the HLA-DPB1 and HLA-DPA1 loci, and provide subtype-specific resolution. Finally, analysis of the additive effects of HLA allele heterozygosity in smokers identified significant associations with several 4-digit HLA alleles, including HLA-B∗08:01, HLA-A∗01:01, HLA-C∗07:01, HLA-DQA1∗05:01, HLA-DRB1∗03:01, and HLA-C∗03:04. Our study provides additional evidence, with added histologic subtype information, that germline HLA-II heterozygosity is inversely associated with lung cancer risk.

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Publication Details

Journal
Human Genetics and Genomics Advances
Published
2026-01-12
DOI
https://doi.org/10.1016/j.xhgg.2026.100567
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
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article

Germline HLA heterozygosity is associated with decreased lung cancer risk

Penella J. Woll, Angeline S. Andrew, James D. McKay, Sanjay Shete et al.
Human Genetics and Genomics Advances
Cancer Immunotherapy and Biomarkers
article

Germline HLA heterozygosity is associated with decreased lung cancer risk

Penella J. Woll, Angeline S. Andrew, James D. McKay, Sanjay Shete, Mattias Johansson, John K. Field, Vikram R. Shaw, Philip Lazarus, Rennert Gad, Risch Angela, Xin-An Wang, Melinda C. Aldrich, Lambertus A. Kiemeney, Guillermo Fernandez-Tardon, Hyun-Sung Lee, Jinyoung Byun, Aage Haugen, Stig Egil Bojesen, Dakai Zhu, Yafang Li, Younghun Han, David Zaridze, Maria Teresa Landi, Matthew B. Schabath, Adonina Tardon, Taotao Tan, H-Erich Wichmann, Stephen Lam, Rayjean J. Hung, Chao Cheng, Shanbeh Zienolddiny, David C. Christiani, Susanne M. Arnold, Christopher Amos, Heike Bickeböller, Mikael Johansson, Demetrios Albanes, Michael Davies, Loïc Le Marchand
article en

Abstract

Heterozygosity at human leukocyte antigen (HLA) loci may improve lung cancer immunosurveillance by increasing recognition of the tumor by the immune system. Previous studies utilizing data from population-level biobanks, such as the United Kingdom Biobank and FinnGen, have identified an association between germline HLA class II (HLA-II) heterozygosity and reduced lung cancer risk in smokers. In the present study, we evaluate the association between HLA heterozygosity and lung cancer in a large case-control study (15,302 cases and 14,580 controls) with imputed HLA allele-type information, comparing differences in HLA heterozygosity between smokers and non-smokers, among lung cancer subtypes, and at 2- and 4-digit HLA allele resolution. We identify a strong protective association of HLA-II heterozygosity in smokers compared to non-smokers, particularly at the HLA-DPB1 and HLA-DPA1 loci, and provide subtype-specific resolution. Finally, analysis of the additive effects of HLA allele heterozygosity in smokers identified significant associations with several 4-digit HLA alleles, including HLA-B∗08:01, HLA-A∗01:01, HLA-C∗07:01, HLA-DQA1∗05:01, HLA-DRB1∗03:01, and HLA-C∗03:04. Our study provides additional evidence, with added histologic subtype information, that germline HLA-II heterozygosity is inversely associated with lung cancer risk.

Human Genetics and Genomics AdvancesVol. 7(2)
Dartmouth College (US), University of Hawaiʻi at Mānoa (US), BC Cancer Agency (CA), National Institutes of Health (US), University of Hawaii System (US), National Institute of Occupational Health (NO), Massachusetts Department of Public Health (US), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), University of Kentucky (US), Radboud University Nijmegen (NL), University of Liverpool (GB), Universidad de Oviedo (ES), University of New Mexico (US), Baylor College of Medicine (US), University of Salzburg (AT), Lunenfeld-Tanenbaum Research Institute (CA), Heidelberg University (DE), Roy Castle Lung Cancer Foundation (GB), Markey Cancer Center (US), Copenhagen University Hospital (DK), Radboud University Medical Center (NL), Helmholtz Zentrum München (DE), Moffitt Cancer Center (US), Massachusetts General Hospital (US), Russian Cancer Research Center NN Blokhin (RU), Carmel Medical Center (IL), Universitätsmedizin Göttingen (DE), Houston Institute for Clinical Research (US), Hospital Universitario Central de Asturias (ES), National Cancer Institute (US), New Mexico Cancer Center (US), National Medical Research Center of Cardiology (RU), Instituto de Investigación Sanitaria del Principado de Asturias (ES), Centre international de recherche sur le cancer (FR), University of Hawaii Cancer Center, University at Buffalo, State University of New York (US), University of Göttingen (DE), Vanderbilt University Medical Center (US), Umeå University (SE), University of Sheffield (GB)
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Openalex Percentile: Top 91%
Cancer Immunotherapy and Biomarkers
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