Integrative Analysis of Head and Neck Cancer Identifies Two Biologically Distinct HPV and Three Non-HPV Subtypes

Purpose: Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment. Experimental Design: Here, we use gene expression-based consensus clustering, copy number profiling, and human papillomavirus (HPV) status on a clinically homogenous cohort of 134 locoregionally advanced HNSCCs with 44% HPV+ tumors together with additional cohorts, which in total comprise 938 tumors, to identify HNSCC subtypes and discover several subtype-specific, translationally relevant characteristics. Results: We identified five subtypes of HNSCC, including two biologically distinct HPV subtypes. One HPV+ and one HPV− subtype show a prominent immune and mesenchymal phenotype. Prominent tumor infiltration with CD8+ lymphocytes characterizes this inflamed/mesenchymal subtype, independent of HPV status. Compared with other subtypes, the two HPV subtypes show low expression and no copy number events for EGFR/HER ligands. In contrast, the basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype, negative HPV-status, as well as strong hypoxic differentiation not seen in other subtypes. Conclusion: Our five-subtype classification provides a comprehensive overview of HPV+ as well as HPV− HNSCC biology with significant translational implications for biomarker development and personalized care for patients with HNSCC. Clin Cancer Res; 21(4); 870–81. ©2014 AACR.

[1]  M. Dolled-Filhart,et al.  A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV–associated head and neck (H/N) cancer. , 2014 .

[2]  Yusuke Nakamura,et al.  Correlation of T-cell inflamed phenotype with mesenchymal subtype, expression of PD-L1, and other immune checkpoints in head and neck cancer. , 2014 .

[3]  M. Czyz,et al.  The heterogeneous immune microenvironment in breast cancer is affected by hypoxia-related genes. , 2014, Immunobiology.

[4]  J. Taube,et al.  Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. , 2013, Cancer research.

[5]  Christopher R. Cabanski,et al.  Molecular Subtypes in Head and Neck Cancer Exhibit Distinct Patterns of Chromosomal Gain and Loss of Canonical Cancer Genes , 2013, PloS one.

[6]  M. Dimopoulos,et al.  VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2 , 2012, British Journal of Cancer.

[7]  J. Bussink,et al.  Expression of EGFR under tumor hypoxia: identification of a subpopulation of tumor cells responsible for aggressiveness and treatment resistance. , 2012, International journal of radiation oncology, biology, physics.

[8]  R. Mangues,et al.  Gene expression signatures and molecular markers associated with clinical outcome in locally advanced head and neck carcinoma. , 2012, Carcinogenesis.

[9]  Steven J. M. Jones,et al.  Subgroup-specific structural variation across 1,000 medulloblastoma genomes , 2012, Nature.

[10]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[11]  S. Faivre,et al.  Safety and efficacy of panitumumab (pmab) in HPV-positive (+) and HPV-negative (-) recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Analysis of the global phase III SPECTRUM trial. , 2012 .

[12]  A. Pause,et al.  An oxygen-regulated switch in the protein synthesis machinery , 2012, Nature.

[13]  C. Sautès-Fridman,et al.  The immune contexture in human tumours: impact on clinical outcome , 2012, Nature Reviews Cancer.

[14]  Esther Kim,et al.  Human papillomavirus and rising oropharyngeal cancer incidence in the United States. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  R. Gibbs,et al.  Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1 , 2011, Science.

[16]  A. McKenna,et al.  The Mutational Landscape of Head and Neck Squamous Cell Carcinoma , 2011, Science.

[17]  A. Jemal,et al.  Cancer statistics, 2011 , 2011, CA: a cancer journal for clinicians.

[18]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[19]  David A. Cheresh,et al.  Integrins in cancer: biological implications and therapeutic opportunities , 2010, Nature Reviews Cancer.

[20]  Christopher R. Cabanski,et al.  Lung Squamous Cell Carcinoma mRNA Expression Subtypes Are Reproducible, Clinically Important, and Correspond to Normal Cell Types , 2010, Clinical Cancer Research.

[21]  Kakajan Komurov,et al.  Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes , 2010, Proceedings of the National Academy of Sciences.

[22]  K. Ang,et al.  Human papillomavirus and survival of patients with oropharyngeal cancer. , 2010, The New England journal of medicine.

[23]  Matthew D. Wilkerson,et al.  ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking , 2010, Bioinform..

[24]  R. Seruca,et al.  Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells , 2010, Oncogene.

[25]  E. Repasky,et al.  Hypoxia-driven immunosuppression: A new reason to use thermal therapy in the treatment of cancer? , 2010, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[26]  Yuan Qi,et al.  Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA , IDH 1 , EGFR , and NF 1 Citation Verhaak , 2010 .

[27]  E. Neilson,et al.  Biomarkers for epithelial-mesenchymal transitions. , 2009, The Journal of clinical investigation.

[28]  A. Nobel,et al.  Supervised risk predictor of breast cancer based on intrinsic subtypes. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  J. Parker,et al.  A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle. , 2009, Cancer research.

[30]  D. Rickman,et al.  Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays , 2008, Oncogene.

[31]  A. Albino,et al.  Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells , 2008, BMC Cancer.

[32]  N. Hanna.  Open-Label, Uncontrolled, Multicenter Phase II Study to Evaluate the Efficacy and Toxicity of Cetuximab As a Single Agent in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Who Failed to Respond to Platinum-Based Therapy , 2008 .

[33]  Li Mao,et al.  Transcriptomic dissection of tongue squamous cell carcinoma , 2008, BMC Genomics.

[34]  E. Lander,et al.  Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma , 2007, Proceedings of the National Academy of Sciences.

[35]  A. Markoe,et al.  Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. , 2007, The New England journal of medicine.

[36]  A. Schueler,et al.  Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  K. Tanabe,et al.  Cancer immunoediting from immune surveillance to immune escape , 2007, Immunology.

[38]  Crispin J. Miller,et al.  Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers. , 2007, Cancer research.

[39]  Gavin D. Grant,et al.  Common markers of proliferation , 2006, Nature Reviews Cancer.

[40]  Yu Shyr,et al.  Gene Expression Differences Associated with Human Papillomavirus Status in Head and Neck Squamous Cell Carcinoma , 2006, Clinical Cancer Research.

[41]  R. Ferris,et al.  Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. , 2005, Cancer Research.

[42]  C. Perou,et al.  Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. , 2004, Cancer cell.

[43]  E. Gerner,et al.  Polyamines and cancer: old molecules, new understanding , 2004, Nature Reviews Cancer.

[44]  G. Sauter,et al.  E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer , 2004, Oncogene.

[45]  Gang Liu,et al.  Effects of cigarette smoke on the human airway epithelial cell transcriptome. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[46]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[47]  D. Brachman,et al.  Molecular biology of head and neck cancer. , 1994, Seminars in oncology.

[48]  S. Taylor.  Head and neck cancer. , 1991, Cancer chemotherapy and biological response modifiers.

[49]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.