Abstract B046: Integrating genetic ancestry and social determinants of health reveals context-dependent genetic susceptibility to laryngeal cancer

Abstract

Laryngeal cancer is characterized by persistent racial disparities. Self-identified race and ethnicity (SIRE) may not adequately capture biologically relevant population heterogeneity. Because SIRE conflates biological ancestry with social and environmental exposures, we examined how genetic susceptibility variants, genetically inferred ancestry (GIA), and social determinants of health (SDoH) contribute to laryngeal cancer risk. Using data from the All of Us Research Program, we conducted a 1:4 age- and sex-matched case-control study including 482 primary laryngeal cancer cases and 1,928 controls. GIA was quantified using continental ancestry proportions and compared with SIRE. Multivariable logistic regression models were fitted with laryngeal cancer status as the outcome to evaluate associations between candidate susceptibility single nucleotide polymorphisms (SNPs), GIA, SIRE, and SDoH domains. SNP×GIA and SNP×SDoH interactions were evaluated in separate models, adjusting for age, sex, smoking, alcohol use, and genetic principal components (PC1–PC16). Significance was defined as p<0.05. Concordance between GIA and SIRE was high for European (92.26%) and African ancestry (85.88%) but low for Native American ancestry (<10%). Hispanic participants without race reporting demonstrated 82.05% concordance with Native American ancestry. SNP×GIA interaction models revealed significant associations between ERCC1rs11615 (p.Asn118Asn) and Native American ancestry (aOR=0.89, 95% CI: 0.80–0.99), ERCC2 rs50871 (A>C) and East Asian ancestry (aOR=0.65, 95% CI: 0.48–0.88), and TP53 rs1042522 (p.Arg72Pro), ADH1B rs1229984 (p.Arg48His), and RAD51 rs1801321 (172G>T) with Middle Eastern/North African ancestry (aORs as observed in interaction models).Among Black participants, TP53 rs1042522 (aOR=2.04, 95% CI:1.12–3.70) and RAD51 rs1801321 (aOR=1.94, 95% CI:1.09–3.45) were associated with higher odds of laryngeal cancer. SNP×SDoH interaction models identified significant interaction effects between RAD51 rs1801321 and low social support (aOR=2.35, 95% CI: 1.07–5.14), high neighborhood disorder (aOR=2.56, 95% CI: 1.09–6.02), poor neighborhood safety (aOR=2.30, 95% CI: 1.02–5.20), poor housing quality (aOR=3.67, 95% CI: 1.17–11.47), and religious service attendance (aOR=0.43, 95% CI: 0.19–0.97). Additional interactions were observed for ERCC2 rs50871 with low social support and ERCC1 rs11615 with moderate-to-high psychological stress. Beyond SIRE, genetically inferred ancestry and social determinants of health each modified genetic susceptibility to laryngeal cancer, while SIRE poorly captured ancestry among admixed participants. Notably, susceptibility signals observed among Black participants overlapped with interactions involving adverse social conditions, suggesting that some associations attributed to genotype may reflect the embodiment of social exposures. These findings support jointly modeling GIA and SDoH in cancer disparities research and warrant replication before informing risk assessment. Joab O. Odera, Morgan C. Byrd, Oyomoare Osazuwa-Peters, Vincent D’ Anniballe, Xihao Li, Rong Jiang, Nosayaba Osazuwa-Peters. Integrating genetic ancestry and social determinants of health reveals context-dependent genetic susceptibility to laryngeal cancer [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr B046.