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American Head & Neck Society
Annual Meeting, April 10-11, 2013
JW Marriott Grande Lakes
Orlando, Florida

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MULTITIER COMPUTATIONAL GENETIC ANALYSIS IDENTIFIES IMMUNE PATHWAYS ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO HPV-ASSOCIATED HEAD AND NECK CANCER

Presentation: P004
Topic: Basic Science - Immunology
Type: Poster
Date: Wednesday - Thursday, April 10 - 11, 2013
Session: Designated Poster viewing times
Authors: Chaya Levovitz, Sarah Alshawish, Weijia Zhang, PhD, Paolo Boffetta, MD, MPH, Andrew Sikora, MD, PhD
Institution(s): Mount Sinai School of Medicine

 
OBJECTIVES: While exposure to HPV is nearly ubiquitous by young adulthood, only a minority of those exposed develop oropharyngeal cancer (OPC). This raises the possibility that the host immune response may modulate susceptibility to HPV-related head and neck cancer. The overall goal of this project is to identify candidate immune-related genes (IRG) and pathways associated with an increased risk of developing virally-mediated head and neck squamous cell carcinoma (HNSCC).

STUDY DESIGN: Data from a Genome Wide Association Study (GWAS) performed by the International Head and Neck Cancer Epidemiology Consortium (INHANCE) was evaluated for associations between genetic variants in candidate immune related genes and the risk of developing OPC. This study included 3 tiers of investigation, single gene, pathway, and protein-protein interaction analysis and the concordance between them.

METHODS: An association analysis was performed on the INHANCE GWAS dataset with over 300,000 SNPs using a hypothesis driven multi-candidate gene approach. GWAS analyses were performed on all head and neck cancer samples and then limited to samples from patients with oropharyngeal cancer. Alterations in gene pathways significantly associated with OPC were identified using MAGENTA, a gene set enrichment analysis (GSEA) platform. Over 10,000 biological pathways from publically curated databases were tested for enrichment. Gene-gene and protein-protein interactions were investigated by analyzing the physical connectivity among genes or proteins encoded for by the genes, in loci associated to disease according to interactions reported in the literature. Computational platforms used for protein-protein and gene-gene interactions analysis included DAPPLE and GRAIL .

RESULTS: Single SNP analysis of the GWAS revealed 15 immune related genes to be significantly associated with OPC. These genes were substantially more strongly associated with OPC than with all head and neck cancers. Pathway analysis demonstrated several immune pathways were significantly enriched for in the OPC GWAS data set. These pathways clustered into immune specific categories highlighting the immune processes related to development of OPC. These categories include 7 toll-like receptor (TLR) pathways, 3 additional innate immunity pathways, 3 T cell activation pathways, 3 cell death pathways, and 6 NFKB-related pathways. Protein-protein and gene-gene interaction analysis confirmed that there are statistically significant immune specific -interactions clustering in immune processes such as TGFB signaling, TH1/TH2 balance and innate immunity. These statistically significant pathways and protein-protein interactions associated with OPC were not significantly associated with all head and neck cancers.

CONCLUSION: Using a multitier computational genetic approach to analyze the INHANCE HNSCC GWAS, we have identified several immune specific processes that are associated with an increased susceptibility to OPC, the head and neck subsite most associated with HPV. Several of these genes have been confirmed on all three analytical levels including TGFBR1, SOC5, IL10, and IL1RL1. These associations are far stronger for OPC than for all head and neck cancers, suggesting they may play a role in processes uniquely relevant to virally-induced cancer. Genes and pathways identified in this study may provide clues to pathogenic mechanisms driving the acquisition of virally-related HNSCC.

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