The highest tertile of biological age accelerations () is associated with a 42.4% increased risk of incident endometrial cancer (EC).
Both KDM and PhenoAge residual metrics are significantly linked to increased risk of incident EC.
In fully adjusted models, highest BAA levels show hazard ratios (HRs) of 1.278 for KDM and 1.424 for PhenoAge, indicating a higher risk compared to the lowest group.
Population-attributable fractions for KDM and PhenoAge residuals are 7.84% and 9.78%, respectively, suggesting a meaningful contribution to EC risk.
High genetic risk combined with high BAA is significantly associated with EC incidence, with HRs reaching up to 2.226 for PhenoAge.
Higher levels of PhenoAge residual consistently correlate with increased risk of EC, regardless of genetic background.
Simplified
BACKGROUND: Endometrial cancer (EC) is one of the gynecologic malignancy cancer with increasing incidence and mortality rates, partly due to aging populations and genetic risks. This study explores the associations between biological age accelerations () and risk of incident EC and assesses the joint effect of genetic factors and BAA.
MATERIALS AND METHODS: Based on the UK Biobank cohort, 132 315 women participants were included for primary analysis and 124 119 white participants for genetic risk analysis. Biological age (BA) was calculated using the Klemera-Doubal (KDM) and PhenoAge method based on clinical biomarkers. The authors calculated two metrics for BAA (including KDM residual and PhenoAge residual) using residual analysis, comparing them against chronological age. The risk of incident EC was evaluated using multivariable Cox proportional-hazards models, adjusting for relevant covariates. Polygenic risk scores () were computed from known EC-associated SNPs.
RESULTS: Both KDM and PhenoAge residual, were significantly associated with increased EC risk. In fully adjusted models, the highest tertile of KDM and PhenoAge residual was significantly associated with incident EC compared with the lowest group, with HRs of 1.278 ( P =0.0044) and 1.424 ( P <0.0001), repectively. The population-attributable fractions were 7.84% for KDM residual ( P =0.0044), 9.78% for PhenoAge residual ( P =0.0005), and 8.47% for genetic risk ( P =0.0005). Additionally, joint associations of BAA and genetic risk with incident EC was evaluated. Compared with low genetic risk and low BAA, high genetic risk and high BAA was significantly associated with the incidence of EC with HRs of up to 2.172 (95% CI: 1.592-2.963) for KDM and 2.226 (95% CI: 1.640-3.022) for PhenoAge. Overall, higher levels of PhenoAge residual were consistently associated with an increased risk of incident EC, regardless of genetic risk.
CONCLUSION: BAA and genetics both enhance the risk of incident EC. The effect of the PhenoAge residual is greater than that of the investigated genes, which in turn is greater than that of the KDM residual. These findings highlight the importance of considering both BAA and genetic factors in EC prevention.
Key numbers
1.278
Increase in EC Risk (KDM residual)
Hazard ratio for highest tertile vs. lowest tertile of KDM residual.
1.424
Increase in EC Risk (PhenoAge residual)
Hazard ratio for highest tertile vs. lowest tertile of PhenoAge residual.
9.78%
Population-Attributable Fraction for PhenoAge
Estimated contribution of PhenoAge residual to incident endometrial cancer cases.
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The authors declare that they have no financial conflict of interest with regard to the content of this report. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
