Exome Sequencing for Head and Neck Cancer Predisposition Genes

IntroductionWhile genome-wide association studies (GWAS) have identified several common variants associated with head and neck cancer (HNC) risk, large-scale sequence-based studies to evaluate the contribution of rare variants to head and neck cancer risk have not been conducted. The aim of our study was to identify head and neck cancer predisposition genes with exome and targeted sequencing and to assess interactions between the head and neck cancer susceptibility genes and cigarette smoking. MethodsWe conducted gene-based and gene-set-based rare-variant case-control analyses to identify germline susceptibility genes for HNC risk. In Phase 1, we generated and analyzed an exome dataset consisting of 220 familial HNC cases to construct a candidate risk gene panel of 501 genes. In Phase 2, we performed targeted sequencing of the candidate gene panel in 2,134 HNC cases and 2,072 controls matched by age, race, and ethnicity. We then conducted rare variant association analysis, incorporating the Phase 2 dataset together with 531 HNC cases and 119,716 cancer-free controls from UK Biobank whole-exome sequencing data via meta-analysis. We then estimated effect sizes of rare variant classes in known and newly implicated HNC susceptibility genes and pathways for HNC risk. ResultsWe identified 27 genes with nominally significant meta p < 0.05 among the 501 genes evaluated in Phase 2, including six known cancer predisposition genes, BRCA1, BRCA2, RAD51B, BAP1, APC, and MUTYH. Loss-of-function (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. Individuals who only smoked had an OR for head and neck cancer risk of 2.97 (95%CI=2.65, 3.33), individuals who only carried LoF or predicted damaging variants in the DNA homologous recombination repair genes had an OR of 1.74 (95%CI=1.14, 262), and individuals who were carriers and smokers had an OR of 5.24 (95%CI=3.74, 7.32). ConclusionsWe observed associations with HNC risk for DNA repair pathway genes associated with breast cancer and polyposis colorectal cancer. We also observed suggestive interactions between these variants in these genes and cigarette smoking. Our results indicate that smokers with pathogenic variants in the DNA repair genes implicated in this study are at [~]5-fold risk of developing HNC.