Genome-wide association study of never-smoking non-drinking young adults developing oral squamous cell carcinoma

Background: Germline risk variants for oral squamous cell carcinoma (OSCC) in never-smoking non-drinking (NSND) young adults (YA) are poorly characterized and genome-wide association studies focusing on NSND YA OSCC are lacking. This study aims to evaluate if rare germline variants are associated with NSND YA OSCC. Methods: We conducted a retrospective, single-center Canadian cohort study of patients who underwent primary surgery for OSCC between 2010 and 2024. Genome-wide association analyses were performed for three comparisons: 1- NSND YA (n = 10) vs. other OSCC (n = 150), 2- all-ages NSND (n = 29) vs. ever-smoker and/or drinker (n = 131), and 3- any risk factor YA OSCC (n = 22) vs. age ≥ 45 (n = 138). A polygenic risk score for age at OSCC diagnosis was derived from clumping + thresholding. Results: We included 160 patients of European ancestry with a diagnosis of OSCC: 22 YA and 29 NSND patients; 10 patients were both YA and NSND. YA cases predominantly involved the oral tongue. One rare variant, rs191595756, showed a suggestive association with NSND YA OSCC (p = 3.3e-06), but did not reach genome-wide significance. This variant is located in an intron of LINC00944 and in an exon of LINC02824. No rare variant signals were supported in the all-ages NSND and any risk factor YA OSCC. None of the identified variants is reported in ClinVar. An exploratory polygenic risk score composed of 13 index variants was constructed. It is independent of NSND or ever-smoker and/or drinker status. It is also independent of oral tongue or other oral cavity primary cancer site. Conclusions: This is the first study investigating genome-wide associations in NSND YA OSCC. No single germline variant of genome-wide significance associated with NSND YA OSCC occurrence was found, suggesting a polygenic architecture. Larger, multicentric studies are needed to validate a polygenic risk score specifically predictive of NSND YA OSCC risk.