Abstract
In this multi-ancestry genome-wide association study (GWAS) and fine mapping study of head and neck squamous cell carcinoma (HNSCC) subsites, we analysed 19,073 cases and 38,857 controls and identified 29 independent novel loci. We provide robust evidence that a 3' UTR variant in TP53 (rs78378222, T>G) confers a 40% reduction in odds of developing overall HNSCC. We further examine the gene-environment relationship of BRCA2 and ADH1B variants demonstrating their effects act through both smoking and alcohol use. Through analyses focused on the human leukocyte antigen (HLA) region, we highlight that although human papilloma virus (HPV)(+) oropharyngeal cancer (OPC), HPV(-) OPC and oral cavity cancer (OC) all show GWAS signal at 6p21, each subsite has distinct associations at the variant, amino acid, and 4-digit allele level. We also defined the specific amino acid changes underlying the well-known DRB1*13:01-DQA1*01:03-DQB1*06:03 protective haplotype for HPV(+) OPC. We show greater heritability of HPV(+) OPC compared to other subsites, likely to be explained by HLA effects. These findings advance our understanding of the genetic architecture of head and neck squamous cell carcinoma, providing important insights into the role of genetic variation across ancestries, tumor subsites, and gene-environment interactions.