HLA-II heterozygosity associated with reduced lung cancer risk in smokers

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Population-level immunogenetic variation is a factor underlying lung cancer risk in current and former smokers, a large study has found.

Researchers used genetic and clinical data from two large-scale population cohorts – UK Biobank and FinnGen – together with multi-modal genomic analyses of non-malignant and lung tumour samples to evaluate the effect of human leukocyte antigen (HLA) heterozygosity on lung cancer risk.

The analysis found heterozygosity at the HLA class II (HLA-II) loci was associated with reduced risk of lung cancer over more than a decade of follow-up, study authors wrote in the journal Science

Of note, HLA-II heterozygosity was associated with reduced risk of lung cancer in both current and former smokers, but not never-smokers.

This suggested that smoking-derived antigens might augment the immune response to early neoplastic disease, they wrote.

In contrast, HLA-II homozygosity conferred substantial lifetime risk of disease (13.9% for current smokers in the UK Biobank cohort) and was independent of known clinical and genetic risk factors.

Co-senior author Dr Diego Chowell, assistant professor of oncological sciences, and immunology and immunotherapy at the Icahn School of Medicine at Mount Sinai in New York, which led the study in collaboration with the University of Helsinki and Massachusetts General Hospital, said the findings challenged conventional thinking by demonstrating that immune genetics, specifically HLA-II heterozygosity, played a significant role in lung cancer risk, especially among smokers.

Dr Chowell said: ‘Further, when we added polygenic risk scores – which is a measure of genetic predisposition based on multiple genes – to the analysis, it increased the lifetime risk of lung cancer, specifically in smokers who have identical versions of the HLA-II genes.’

Understanding HLAs and cancer risk

HLAs are cell surface molecules that recognise antigenic peptides and present them to T-cells to initiate an immune response.

In lung cancer, genetic variation in the HLA locus was known to be linked to tumour evolution and treatment outcomes, but it was unclear whether HLA polymorphisms reduced lung cancer risk, the researchers explained.

This study was designed to test the heterozygote advantage hypothesis, which is a foundational principle of the evolution of the HLA system and of HLA-mediated protection against disease.

‘According to this hypothesis, individuals heterozygous at HLA are afforded greater protection against disease because they present more antigens for T-cell recognition through their two different HLA allomorphs than do homozygous individuals and consequently clear infected or neoplastic cells more efficiently,’ the researchers wrote.

The data underscored the role of immunosurveillance in protecting against lung cancer, the researchers said.

‘The association of HLA-II heterozygosity with reduced risk of lung cancer implies that genetic variation in immune-surveillance is a feature of cancer susceptibility, together with environmental exposures, hereditary risk and DNA replication errors,’ they said.

The findings broadened the understanding of the role the host immune system played in cancer risk and might motivate the incorporation of immunogenetics into lung cancer screening programmes, the study authors concluded.

‘A greater understanding of immunogenetic determinants of cancer risk, including genetic variation in HLA and other immune genes and pathways commonly associated with autoimmune and infectious diseases, may foster the development of improved strategies for cancer prevention,’ they wrote.

The findings suggested that current or former smokers homozygous at HLA-II could be considered at an earlier age for low-dose computed tomographic (LDCT) screening, which might reduce lung cancer mortality.

Whether the combination of genotype-driven risk assessment and LDCT reduced lung cancer mortality compared with either method alone should be comprehensively investigated in a future prospective clinical trial, they said.


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