Targeted Gene Sequencing for Head and Neck Cancer Candidate Genes in the Nepal case-control study

Head and Neck cancer (HNC) remains a major global cancer burden, with high incidence and mortality in low- and middle-income countries. Although several genetic variants associated with HNC risk have been identified, cancer predisposition genes in underrepresented populations remain poorly understood. We conducted a hospital-based case-control study at B.P. Koirala Memorial Cancer Hospital in Nepal with 315 HNC cases and 323 controls. Demographic, lifestyle, and clinical data were collected through in-person interviews. Targeted gene sequencing of 493 candidate HNC risk genes were performed, followed by gene- and pathway-based association analyses, and clinical annotation of the identified variants. Consistent with prior findings, HNC incidence increased significantly with alcohol and cigarette use, lower education, and lower socio-economic status. Gene-based analyses identified several genes with suggestive associations prior to multiple-testing adjustment, including HSPG2, KRT6B, SLC4A2, and FREM1. Similarly, no pathways remained statistically significant after adjustment. However, it identified potential biological processes, including extracellular matrix organization, epithelial differentiation, and transcription regulation. Analysis of six cancer predisposition genes (APC, BAP1, BRCA1, BRCA2, RAD51B, and MUTYH) identified pathogenic and likely pathogenic variants with clinical relevance, although no significant enrichment was observed between cases and controls. This study provides the first targeted sequencing analysis combined with epidemiological data for HNC in the Nepalese population, an underrepresented high-risk group. While no significant genetic associations were identified, clinically relevant rare variants were detected. Larger studies in South Asian populations are needed to improve the detection of rare variants and to inform risk assessment.