title: TGFβ receptor 1: an immune susceptibility gene in HPV-associated cancer.
abstract: 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. TGFβR1, 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 TGFβR1 containing p38-MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV(+) head and neck cancer tumors. These concordant analyses implicate TGFβR1 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 TGFβR1/TGFβ 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.
authors.affiliation: The Icahn School of Medicine at Mount Sinai, New York, New York. Department of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York. Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Chaya
authors.initials: C
authors.lastname: Levovitz
authors.affiliation: SciLifeLab Uppsala, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: SciLifeLab Uppsala, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Ivansson
authors.affiliation: SciLifeLab Uppsala, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.affiliation: The Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: John P
authors.initials: JP
authors.lastname: Finnigan
authors.affiliation: The Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sara
authors.initials: S
authors.lastname: Alshawish
authors.affiliation: Mount Sinai Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Mount Sinai Institute for Genomics and Multiscale Biology, New York, New York.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: The Icahn School of Medicine at Mount Sinai, New York, New York. Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Marshal R
authors.initials: MR
authors.lastname: Posner
authors.affiliation: The Icahn School of Medicine at Mount Sinai, New York, New York. Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Immunology, Genetics and Pathology, Tisch Cancer Institute, New York, New York.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Genden
authors.affiliation: The Icahn School of Medicine at Mount Sinai, New York, New York. Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Immunology, Genetics and Pathology, Tisch Cancer Institute, New York, New York.
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.affiliation: The Icahn School of Medicine at Mount Sinai, New York, New York. Department of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Immunology, Genetics and Pathology, Tisch Cancer Institute, New York, New York. andrew.sikora@bcm.edu.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Sikora
mesh_terms: D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000276:immunology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I