A Genome-wide Association study of Buccal Mucosa Cancer in India and Multi-ancestry Meta-analysis Identifies Novel Risk Loci and Gene-environment Interactions

Genome-wide association studies (GWAS) of oral cancers (OC) to date have focused predominantly on European Ancestry (EA) populations. India faces an excess burden of OC, but the most common site of occurrence is the cancer of the buccal mucosa, which is relatively rare in EA populations. We conducted a GWAS of buccal mucosa cancer (BMC) comprising 2,160 BMC cases and 2,325 controls from different geographical locations in India. Single-SNP association tests detected one novel locus (6q27) and one novel signal within the known OC risk locus 5p13.33, at the genome-wide significance level (P-value<5X10 ^-8 ). We additionally conducted a GWAS of 397 BMC cases and 439 controls from Taiwan and performed multi-ancestry GWAS meta-analysis of OC on 5255 cases and 8748 controls across EA, Indian and Taiwanese populations. We identified a novel risk locus harbouring the tumour suppressor gene NOTCH1 through a gene-level analysis of the multi-ancestry GWAS data. Pathway analysis suggested that PD-1 signalling, and Interferon Gamma Signalling may be important in the aetiology of BMC. Within data from the Indian BMC GWAS, we further identified statistically significant evidence of both multiplicative interactions (P-value=0.026) indicating stronger polygenic risk of BMC among individuals with history of chewing tobacco compared to those without. Our study provides insights into the etiologies of BMC in India, highlighting both its similarities and differences with other types of oral cavity cancers, as well as the interactions between polygenic gene score and tobacco chewing.