Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical (CC) and oropharyngeal cancer (OPC). Since host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to OPC and other HPV-associated cancers by performing a multitier integrative computational analysis with OPC data from a head and neck cancer (HNC) genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein-protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with OPC. TGFBR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the HNC GWAS limited to HPV-seropositive cases, and an independent CC GWAS. The TGFBR1 containing p38-MAPK pathway was significantly associated with OPC and CC, and TGFBR1 was overexpressed in OPC, CC, and HPV+HNC tumors. These concordant analyses implicate TGFBR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to OPC, and implicates TGFBR1/TGFB signaling in the development of both OPC and CC. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer.


