Subtypes of HPV-positive head and neck cancers are associated with HPV characteristics, copy number alterations, PIK3CA mutation, and pathway signatures

Yanxiao Zhang, Lada A. Koneva, Shama Virani, Anna E. Arthur, Alisha Virani, Pelle B. Hall, Charles D. Warden, Thomas E. Carey, Douglas B. Chepeha, Mark E. Prince, Jonathan B. McHugh, Gregory T. Wolf, Laura S. Rozek, Maureen A. Sartor

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: There is substantial heterogeneity within human papillomavirus (HPV)-associated head and neck cancer (HNC) tumors that predispose them to different outcomes; however, the molecular heterogeneity in this subgroup is poorly characterized due to various historical reasons. Experimental Design: We performed unsupervised gene expression clustering on deeply annotated (transcriptome and genome) HPV+HNCsamples from two cohorts (84 total primary tumors), including 18 HPV-HNC samples, to discover subtypes and characterize the differences between subgroups in terms of their HPV characteristics, pathway activity, whole-genome somatic copy number alterations, and mutation frequencies. Results: We identified two distinct HPV+ subtypes (namely HPV-KRT and HPV-IMU). HPV-KRT is characterized by elevated expression of genes in keratinocyte differentiation and oxidation-reduction process, whereas HPV-IMU has strong immune response and mesenchymal differentiation. The differences in expression are likely connected to the differences in HPV characteristics and genomic changes. HPV-KRT has more genic viral integration, lower E2/E4/E5 expression levels, and higher ratio of spliced to full-length HPV oncogene E6 than HPV-IMU; the subgroups also show differences in copy number alterations and mutations, in particular the loss of chr16q in HPV-IMU and gain of chr3q and PIK3CA mutation in HPV-KRT. Conclusions: Our characterization of two subtypes of HPV+ HNC tumors provides valuable molecular level information that point to two main carcinogenic paths. Together, these results shed light on stratifications of the HPV+ HNCs and will help to guide personalized care for HPV+ HNC patients. Clin Cancer Res; 22(18); 4735-45.

Original languageEnglish (US)
Pages (from-to)4735-4745
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number18
DOIs
StatePublished - Sep 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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