Background: Despite the decreasing incidence of tobacco-related head and neck cancers (HNC) in the U.S., this decline has been offset by a steady increase in human papillomavirus (HPV)-associated oropharyngeal cancers (OPC). Recent epidemiological evidence suggests that genetic variation in genes influencing immune function plays an important role in HNC susceptibility. However, the effects of such variants on HNC risk are poorly understood.

Methods: Using the U.S. Department of Veterans Affairs Million Veteran Program (MVP) cohort, we phenotyped 2,931 HNC patients (1,188 OPC and 1,743 non-OPC) from the cancer registry and 11,724 frequency-matched cancer-free controls. We used a pathway-based approach to elucidate the relationship between HNC risk and 22,950 common variants in 1,460 immune-related genes (Axiom Biobank Array). Odds ratio (OR) and 95% confidence interval (CI) were calculated by multivariate logistic regression using an additive model, with adjustment for race/ethnicity, age, gender, smoking status, alcohol consumption, body mass index (BMI), and the principal components derived from all variants and ancestry informative markers. A false discovery rate (FDR) adjusted P-value < 0.1 was used to identify significant association signals.

Results: The vast majority of MVP participants included in this analysis were non-Hispanic white (79%) and male (96%). HNC patients had a mean age at diagnosis of 64 years. Our single-variant association analyses led to the identification of 12 variants in nine genes (mapped on five genetic loci) that were associated with HNC susceptibility. Of the 12 top candidates, (1) we discovered four novel variants mapped to three susceptibility genes, including FGF18 rs67585403 (OR 0.91: 0.87-0.96) on 5q35.1, RELA rs7115734 (OR 0.92: 0.88-0.95) on 11q13.1, FANCA rs12931267 (OR 1.18: 1.12-1.24), and rs17233497 (OR 1.15: 1.09-1.25) on 16q24.3; and (2) we found eight variants located in two known loci previously reported with HNC risk, including HLA cluster on 6p21.32 (DOA rs16871297, DQA1 rs9273215 and rs28584179, DQB2 rs9276689, DRA rs3135394, and DRB1 rs116518618) and SMC2 (rs3818625 and rs10820599) on 9q31.1. Furthermore, the stratified analysis showing the effects of HLA cluster variants were more evident in HNC cases with OPC, whereas the novel variants of FGF18, RELA, and FANCA had stronger evidence of associations in those with non-OPC.

Conclusion: We confirmed two known risk loci for HNC while concurrently identifying an additional four novel variants involved in the immune pathway genes that may contribute to HNC susceptibility. This study is in the Veteran population, future research will be needed to expand validation to non-Veteran populations with different race/ethnicity and gender distributions, and to identify potential causal variants by more detailed genetic mapping and functional characterization.

Citation Format: Yanhong Liu, Jennifer R. Kramer, Liang Chen, Zenab I. Yusuf, Vlad Sandulache, Li Jiao, Elizabeth Y. Chiao, Andrew G. Sikora, Donna L. White. Immunogenetic determinants of head and neck cancer in Veterans in the Million Veteran Program cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 870.