Abstract 4175: TGFBR1 and other immune-related genes modify susceptibility to HPV-associated head and neck cancer
Authors: Levovitz Chaya , Chen Dan , Ivansson Emma , Gyllensten Ulf , McKay James , Brennan Paul , Boffetta Paolo , Sikora Andrew 
Published: May 2015

OBJECTIVES: Human papilloma virus (HPV)-related cancer of the oropharynx (OPC) makes up an increasing proportion of head and neck cancers (HNC). Since viral infection and progression to cancer are both strongly influenced by the immune system, the host immune response is one potential determinant of susceptibility to HPV-related cancers. The overall goal of this project is to identify immune-genetic variants associated with an increased risk of developing virally-mediated HNC.

STUDY DESIGN: Data from a HNC Genome Wide Association Study (GWAS) performed by the International Agency for Research on Cancer (IARC) and the Centre National de Gestion (CNG) was evaluated for associations between genetic variants in immune genes and the risk of developing OPC.

METHODS: An association analysis using multivariate logistic regression was performed on the HNC GWAS data limited to OPC. We analyzed all SNPs intersecting immune genes based on Gene Ontology using a multi tier computational approach which included single gene analysis, gene-gene interaction (GGI) analysis, pathway analysis and protein-protein interaction (PPI) analysis. Results were validated in 2 in-silico replications: the HNC GWAS limited to individuals with serologic evidence of HPV infection, and a cervical cancer GWAS.

RESULTS: The OPC GWAS found 17 immune SNPs to be associated with OPC at a significance level of p&lt;10-4 -10-7. GGI analysis demonstrated a high degree of significant functional connection amongst the top ranked immune genes, and PPI analysis identified three significant functional clusters of immune genes related to TGFBR1 signaling, innate immunity, or Th1/Th2 immune balance. Pathway analysis identified multiple immune pathways significantly enriched in the OPC GWAS including 4 cell death, 5 innate immunity, 4 NFKB, 2 T-cell activation, and 4 TGFB signaling pathways. While several immune genes were found to overlap multiple modes of analysis, TGFBR1 intersected all tiers of analysis and was thus selected for validation. Replication in the GWAS dataset limited to serologically HPV+ HNC cases validated 14 out of the 15 significant genes including TGFBR1. Replication in a cervical cancer GWAS demonstrated TGFBR1 to be significantly associated with cancer risk and an identical TGFBR1 containing pathway to be highly significant in both cervical cancer and OPC GWAS.

CONCLUSIONS: The high degree of concordance among multiple independent tiers of analysis, strongly implicates variations in immune-related genes as modulators of susceptibility to HPV-mediated HNC and highlights TGFB signaling as a process potentially dysregulated across HPV-related cancers. Thus data highlights the role of host immunogenetics as a modulator of virally-related cancer risk and the utility of multi-component computational strategies in testing biologically based hypothesis about mechanisms of disease susceptibility.

Citation Format: Chaya Levovitz, Dan Chen, Emma Ivansson, Ulf Gyllensten, James McKay, Paul Brennan, Paolo Boffetta, Andrew Sikora. TGFBR1 and other immune-related genes modify susceptibility to HPV-associated head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4175. doi:10.1158/1538-7445.AM2014-4175