title: Human Papillomavirus Drives Tumor Development Throughout the Head and Neck: Improved Prognosis Is Associated With an Immune Response Largely Restricted to the Oropharynx.
abstract: Purpose In squamous cell carcinomas of the head and neck (HNSCC), the increasing incidence of oropharyngeal squamous cell carcinomas (OPSCCs) is attributable to human papillomavirus (HPV) infection. Despite commonly presenting at late stage, HPV-driven OPSCCs are associated with improved prognosis compared with HPV-negative disease. HPV DNA is also detectable in nonoropharyngeal (non-OPSCC), but its pathogenic role and clinical significance are unclear. The objectives of this study were to determine whether HPV plays a causal role in non-OPSCC and to investigate whether HPV confers a survival benefit in these tumors. Methods Meta-analysis was used to build a cross-tissue gene-expression signature for HPV-driven cancer. Classifiers trained by machine-learning approaches were used to predict the HPV status of 520 HNSCCs profiled by The Cancer Genome Atlas project. DNA methylation data were similarly used to classify 464 HNSCCs and these analyses were integrated with genomic, histopathology, and survival data to permit a comprehensive comparison of HPV transcript-positive OPSCC and non-OPSCC. Results HPV-driven tumors accounted for 4.1% of non-OPSCCs. Regardless of anatomic site, HPV+ HNSCCs shared highly similar gene expression and DNA methylation profiles; nonkeratinizing, basaloid histopathological features; and lack of TP53 or CDKN2A alterations. Improved overall survival, however, was largely restricted to HPV-driven OPSCCs, which were associated with increased levels of tumor-infiltrating lymphocytes compared with HPV-driven non-OPSCCs. Conclusion Our analysis identified a causal role for HPV in transcript-positive non-OPSCCs throughout the head and neck. Notably, however, HPV-driven non-OPSCCs display a distinct immune microenvironment and clinical behavior compared with HPV-driven OPSCCs.
authors.affiliation: Ankur Chakravarthy, Stephen Henderson, Matt Lechner, Andrew Feber, and Tim R. Fenton, UCL Cancer Institute, University College London, London; Stephen M. Thirdborough, Christian H. Ottensmeier, and Gareth J. Thomas, University of Southampton, Southampton, United Kingdom; Xiaoping Su, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Ankur
authors.initials: A
authors.lastname: Chakravarthy
authors.affiliation: Ankur Chakravarthy, Stephen Henderson, Matt Lechner, Andrew Feber, and Tim R. Fenton, UCL Cancer Institute, University College London, London; Stephen M. Thirdborough, Christian H. Ottensmeier, and Gareth J. Thomas, University of Southampton, Southampton, United Kingdom; Xiaoping Su, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Stephen
authors.initials: S
authors.lastname: Henderson
authors.affiliation: Ankur Chakravarthy, Stephen Henderson, Matt Lechner, Andrew Feber, and Tim R. Fenton, UCL Cancer Institute, University College London, London; Stephen M. Thirdborough, Christian H. Ottensmeier, and Gareth J. Thomas, University of Southampton, Southampton, United Kingdom; Xiaoping Su, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Thirdborough
authors.affiliation: Ankur Chakravarthy, Stephen Henderson, Matt Lechner, Andrew Feber, and Tim R. Fenton, UCL Cancer Institute, University College London, London; Stephen M. Thirdborough, Christian H. Ottensmeier, and Gareth J. Thomas, University of Southampton, Southampton, United Kingdom; Xiaoping Su, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Ottensmeier
authors.affiliation: Ankur Chakravarthy, Stephen Henderson, Matt Lechner, Andrew Feber, and Tim R. Fenton, UCL Cancer Institute, University College London, London; Stephen M. Thirdborough, Christian H. Ottensmeier, and Gareth J. Thomas, University of Southampton, Southampton, United Kingdom; Xiaoping Su, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.affiliation: Ankur Chakravarthy, Stephen Henderson, Matt Lechner, Andrew Feber, and Tim R. Fenton, UCL Cancer Institute, University College London, London; Stephen M. Thirdborough, Christian H. Ottensmeier, and Gareth J. Thomas, University of Southampton, Southampton, United Kingdom; Xiaoping Su, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Matt
authors.initials: M
authors.lastname: Lechner
authors.affiliation: Ankur Chakravarthy, Stephen Henderson, Matt Lechner, Andrew Feber, and Tim R. Fenton, UCL Cancer Institute, University College London, London; Stephen M. Thirdborough, Christian H. Ottensmeier, and Gareth J. Thomas, University of Southampton, Southampton, United Kingdom; Xiaoping Su, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.affiliation: Ankur Chakravarthy, Stephen Henderson, Matt Lechner, Andrew Feber, and Tim R. Fenton, UCL Cancer Institute, University College London, London; Stephen M. Thirdborough, Christian H. Ottensmeier, and Gareth J. Thomas, University of Southampton, Southampton, United Kingdom; Xiaoping Su, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
authors.affiliation: Ankur Chakravarthy, Stephen Henderson, Matt Lechner, Andrew Feber, and Tim R. Fenton, UCL Cancer Institute, University College London, London; Stephen M. Thirdborough, Christian H. Ottensmeier, and Gareth J. Thomas, University of Southampton, Southampton, United Kingdom; Xiaoping Su, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Tim R
authors.initials: TR
authors.lastname: Fenton
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000821:virology*; D019175:DNA Methylation; D006258:Head and Neck Neoplasms / Q000821:virology*; D061809:Human Papillomavirus DNA Tests; D006801:Humans; D009959:Oropharyngeal Neoplasms / Q000821:virology; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000821:virology*; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor