Abstract 4083: Ancestral background and germline mutations in head and neck cancer: An analysis of disparities in genetic risk factors using the All of Us database

Background: Head and Neck Cancer (HNC) ranks as the seventh most common cancer globally, yet significant disparities persist in mortality rates across ethnic groups, especially in the United States (US). Hispanic and Non-Hispanic (NH) Black men exhibit higher cancer-specific mortality rates for HNC compared to NH White men, indicating gaps in cancer prevention, early detection, and genetic risk profiling for these groups. The influence of genetic ancestry on HNC risk remains understudied, particularly within Hispanics, who have a diverse ancestral composition. This study aims to elucidate the association between genetic ancestry and HNC, while also analyzing mutations in four genes associated with HNC: FAT1, POLB, TP53, and CDKN2A. Methods: Demographic information, electronic health records, and microarray data for this study was sourced from the All of Us Research Program. A cohort of 2,552 individuals was identified, where half were of HNC cases, and half were demographically matched controls without a cancer diagnosis. Mann-Whitney U test was performed to analyze the differences between ancestry percentages within cancer and non cancer groups. Associations of genetic variants with cancer status or ancestral genetic makeup were assessed with Chi-square tests. Results: Self-reported Hispanic or Latino participants in our cohort had an approximate average of 83% Indigenous American ancestry, 8% European ancestry, 6% African ancestry, 1% Eastern Asian ancestry, 0.6% Southern Asian ancestry, and 0.5% Middle Eastern ancestry. We identified that individuals with a higher percentage of Indigenous American ancestry were more likely to have a negative cancer diagnosis (p<0.05). Conversely, individuals with a higher percentage of European ancestry were more likely to have a positive HNC diagnosis (p<0.01). We did not identify significant results relating African ancestry to the diagnosis of HNC. Six single nucleotide polymorphisms (SNPs) within the four genes studied had a significant association to cancer diagnosis (p<0.05). There was a significant association in two of these SNPs between genotypes and predominant ancestry. Individuals with predominant Indigenous American ancestry were more likely to have the CT genotype for rs3136719 in the POLB gene (p<0.05). For rs3218009 in the CDKN2A gene, individuals with predominant European ancestry were associated with the CG genotype (p<0.05). Conclusions: We identified that a high percentage of Indigenous American ancestry was linked to reduced HNC risk, while a high percentage of European ancestry was associated with increased risk, suggesting ancestry-related germline mutations may influence susceptibility. These findings indicate that the increased mortality rate related to HNC in Black and Latino populations in the US could be more significantly affected by social determinants of health. Citation Format: Mayra S. Haedo-Cruz, Grace E. Vélez-Crespo, Natalie Álamo-Rodríguez, Vivian Colón-López, Julie Dutil, Josué Pérez-Santiago. Ancestral background and germline mutations in head and neck cancer: An analysis of disparities in genetic risk factors using the All of Us database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4083.