Abstract

Background

In squamous carcinomas of the head and neck (HNSCC), the increasing incidence of oropharyngeal cancers (OPSCC) is attributable to HPV infection. Despite commonly presenting at late stage, HPV-driven OPSCC are associated with improved prognosis compared with HPV-negative disease. HPV DNA is also detectable in non-oropharyngeal (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.

Method

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. 464 HNSCCs were similarly classified using DNA methylation data 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-OPSCC. Regardless of anatomic site, HPV+ HNSCCs shared highly similar gene expression and DNA methylation profiles; non-keratinizing, 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-OPSCC.

Conclusion

Our analysis identifies a causal role for HPV in transcript-positive non-OPSCC throughout the head and neck. Notably however, HPV-driven non-OPSCCs display a distinct immune microenvironment and clinical behavior compared with HPV-driven OPSCCs.