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Accelerated Biological Aging Increases the Risk of Head and Neck Cancer: Insights From Genetic Instruments of Epigenetic Clocks.

Jiaqi Wang·Jie Deng·Yifan Xu·Chia-Wen Tsai·Wen-Shin Chang·Yang Deng·Maosheng Huang·Da-Tian Bau·Guojun Li·Jian Gu
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Abstract

Epigenetic clocks are robust biomarkers of biological aging and have been associated with cancer susceptibility. However, the relationship between genetically predicted epigenetic age acceleration and head and neck cancer risk remains unclear. Using a large case-control study of 2189 head and neck squamous cell carcinoma (HNSCC) cases and 2189 age- and sex-matched controls, we investigated the associations between polygenic scores (PGSs) for multiple epigenetic clocks and HNSCC risk, and evaluated their potential causal roles using two-sample Mendelian randomization (MR). Genome-wide association study (GWAS)-identified single nucleotide polymorphisms (SNPs) associated with four epigenetic clocks (HannumAge, HorvathAge, GrimAge, and PhenoAge) were used to construct clock-specific PGSs. Logistic regression models were applied to assess associations between PGSs and HNSCC risk, while MR analyses, including inverse-variance weighted (IVW), weighted median, and MR-Egger methods, were used to infer potential causal relationships. Among the 48 epigenetic clock-associated SNPs, 12 showed nominal associations with HNSCC risk, and one variant (rs2275558 in PBX1) remained significant after Bonferroni correction (OR = 0.67, 95% CI: 0.60-0.76). PGSs for all four epigenetic clocks were higher in cases than in controls. In logistic regression analyses, each standard deviation increase in HannumAge PGS was associated with a 25% higher risk of HNSCC (OR = 1.25, 95% CI: 1.10-1.41), whereas HorvathAge, GrimAge, and PhenoAge PGSs showed weaker positive associations (ORs ranging from 1.06 to 1.10). Individuals in the highest PGS quartile for all four epigenetic clocks exhibiting 14%-25% higher risk than those in the lower three quartiles. MR analyses supported potential causal effects of genetically predicted HannumAge (IVW OR = 1.24 per SD increase, 95% CI: 1.09-1.42) and GrimAge (IVW OR = 1.23 per SD increase, 95% CI: 0.98-1.56) on HNSCC risk, with consistent estimates in weighted median analyses. Our results highlight biological aging as a potential etiologic mechanism for HNSCC and suggest that epigenetic clock-related genetic profiles may improve HNSCC risk stratification.

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HumansPolymorphism, Single NucleotideEpigenesis, GeneticHead and Neck NeoplasmsGenome-Wide Association StudyCase-Control StudiesAgingGenetic Predisposition to DiseaseFemaleGenetic Risk ScoreMaleRisk FactorsMendelian Randomization AnalysisSquamous Cell Carcinoma of Head and NeckAgedMendelian randomizationPGSSNPbiological agingepigenetic clockhead and neck cancerJournal ArticleResearch Support, Non-U.S. Gov't

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Jiaqi Wang, Jie Deng, Yifan Xu, Chia-Wen Tsai, Wen-Shin Chang, Yang Deng, Maosheng Huang, Da-Tian Bau, Guojun Li, Jian Gu. 2026-07-02. Accelerated Biological Aging Increases the Risk of Head and Neck Cancer: Insights From Genetic Instruments of Epigenetic Clocks.. https://doi.org/10.1002/mc.70144

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Aged subjectAging subjectCase-Control Studies subjectEpigenesis, Genetic subjectFemale subjectGenetic Predisposition to Disease subjectGenetic Risk Score subjectGenome-Wide Association Study subjectHumans subjectJournal Article subjectJournal Article; Research Support, Non-U.S. Gov't resourceMale subjectMendelian Randomization Analysis subjectMendelian randomization subjectPolymorphism, Single Nucleotide subject

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