Data from <i>TGF</i>β Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer

Abstract

<div>Abstract<p>Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because 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 oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer 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 oropharyngeal cancer. <i>TGFβR1</i>, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The <i>TGFβR1</i> containing p38–MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and <i>TGFβR1</i> was overexpressed in oropharyngeal cancer, cervical cancer, and HPV<sup>+</sup> head and neck cancer tumors. These concordant analyses implicate <i>TGFβR1</i> signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates <i>TGFβR1</i>/<i>TGFβ</i> signaling in the development of both oropharyngeal cancer and cervical cancer. 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. <i>Cancer Res; 74(23); 6833–44. ©2014 AACR</i>.</p></div>