Subtypes of HPV-Positive Head and Neck Cancers Are Associated with HPV Characteristics, Copy Number Alterations, PIK3CA Mutation, and Pathway Signatures.
OBJECTIVE
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.


METHODS
We performed unsupervised gene expression clustering on deeply annotated (transcriptome and genome) HPV(+) HNC samples 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. ©2016 AACR.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
Yanxiao
Y
Zhang
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
Lada A
LA
Koneva
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan. Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.
Shama
S
Virani
Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.
Anna E
AE
Arthur
Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.
Alisha
A
Virani
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
Pelle B
PB
Hall
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
Charles D
CD
Warden
Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
Thomas E
TE
Carey
Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
Douglas B
DB
Chepeha
Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
Mark E
ME
Prince
Department of Pathology, University of Michigan, Ann Arbor, Michigan.
Jonathan B
JB
McHugh
Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
Gregory T
GT
Wolf
Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan. sartorma@umich.edu rozekl@umich.edu.
Laura S
LS
Rozek
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan. sartorma@umich.edu rozekl@umich.edu.
Maureen A
MA
Sartor
D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006258:Head and Neck Neoplasms / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000150:complications* / Q000821:virology; D015398:Signal Transduction
D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human