Abstract
INTRODUCTION: While common variants have been studied for head and neck cancer (HNC) risk and exome sequencing has been conducted for head and neck tumor tissue samples, large-scale studies of exome sequencing on head and neck cancer risk have not been conducted. Our study aimed to identify head and neck cancer predisposition genes with exome sequencing and to assess interactions between the head and neck cancer susceptibility genes and tobacco use. METHODS: We conducted a case-control analysis to identify germline susceptibility genes for HNC risk. We used whole-exome sequencing data in Phase 1, targeted gene sequencing data in Phase 2 (2,134 HNC cases and 2,072 controls), and publicly available whole-exome sequencing data from the UK Biobank database. We conducted a gene-based association analysis and estimated the effect size of known and novel HNC susceptibility genes and pathways. RESULTS: Six known cancer predisposition genes reached nominal significance (p < 0.05), including BRCA1 , BRCA2 , RAD51B , BAP1 , APC , and MUTYH . Additionally, we identified 21 novel HNC risk genes with meta p-value < 0.05. LoF variants in BRCA1 (OR=5.0, 95% CI: 1.72-14.57), BRCA2 (OR=2.56, 95% CI: 1.22-5.41), and MUTYH (OR=4.84, 95% CI: 1.01-13.86) exhibited significantly elevated effect sizes. APC, BRCA2 , and the DNA repair gene set exhibited borderline interactions with smoking, with synergy indices and 95% confidence intervals of 1.92 [0.98, 3.75], 1.77 [0.91, 3.46], and 1.57 [0.97, 2.54], respectively. CONCLUSIONS: We observed associations with HNC risk for DNA repair pathway genes associated with breast cancer and polyposis colorectal cancer predisposition genes. Potential interactions between these genes and tobacco smoking were also identified. Our study utilized targeted gene sequencing and whole-exome sequencing approaches to identify cancer susceptibility genes, while further studies are needed to confirm the associations observed with HNC risk.