Advertisement

The Genome-Wide Molecular Landscape of HPV-Driven and HPV-Negative Head and Neck Squamous Cell Carcinoma

  • Farhoud Faraji
  • Adrian D. Schubert
  • Luciane T. Kagohara
  • Marietta Tan
  • Yanxun Xu
  • Munfarid Zaidi
  • Jean-Philippe Fortin
  • Carole Fakhry
  • Evgeny Izumchenko
  • Daria A. Gaykalova
  • Elana J. Fertig
Chapter
Part of the Current Cancer Research book series (CUCR)

Abstract

Recent advances in sequencing technology have enabled unprecedented genome-wide characterization of head and neck squamous cell carcinoma (HNSCC). Integrated analyses of publicly available multiplatform high-throughput data have uncovered the vast genomic, epigenetic, and transcriptional diversity of HNSCC. Recognition of human papillomavirus (HPV) involvement in HNSCC carcinogenesis has resulted in the categorization of two HNSCC subtypes (HPV-driven and HPV-negative) with distinct etiologies, molecular properties, clinical features, and prognostic outcomes. Differences in the molecular landscapes of HPV-driven and HPV-negative HNSCC occur genome-wide and encompass changes in genomic, epigenetic, and transcriptional landscapes. Even within each subtype, HNSCC tumors have substantial inter-tumor and intra-tumor molecular heterogeneity. Improving the understanding of the underlying biological function of these complex molecular landscapes through emerging cross-platform genomic analyses is essential to developing more effective diagnostic and therapeutic strategies for HNSCC.

Keywords

Head and neck squamous cell carcinoma Human papillomavirus Genomics Mutation Epigenetics Transcriptomics Heterogeneity Alternative splicing Gene fusion Immunotherapy 

Notes

Conflicts of Interest

The authors have no relevant conflicts of interest to declare.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Torre LA, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Gillison ML, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100(6):407–20.CrossRefPubMedGoogle Scholar
  4. 4.
    Hennessey PT, Westra WH, Califano JA. Human papillomavirus and head and neck squamous cell carcinoma: recent evidence and clinical implications. J Dent Res. 2009;88(4):300–6.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hayashi M, et al. Paired box 5 methylation detection by droplet digital PCR for ultra-sensitive deep surgical margins analysis of head and neck squamous cell carcinoma. Cancer Prev Res (Phila). 2015;8(11):1017–26.CrossRefGoogle Scholar
  6. 6.
    Roh JL, et al. Tissue imprint for molecular mapping of deep surgical margins in patients with head and neck squamous cell carcinoma. Head Neck. 2012;34(11):1529–36.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Santhi WS, et al. Oncogenic microRNAs as biomarkers of oral tumorigenesis and minimal residual disease. Oral Oncol. 2013;49(6):567–75.CrossRefPubMedGoogle Scholar
  8. 8.
    Pena Murillo C, et al. The utility of molecular diagnostics to predict recurrence of head and neck carcinoma. Br J Cancer. 2012;107(7):1138–43.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yi HJ, et al. The role of molecular margins as prognostic factors in laryngeal carcinoma in Chinese patients. Acta Otolaryngol. 2012;132(8):874–8.PubMedGoogle Scholar
  10. 10.
    Faraji F, et al. Molecular mechanisms of human papillomavirus-related carcinogenesis in head and neck cancer. Microbes infect. 2017;19:464.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Fakhry C, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261–9.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ang KK, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lydiatt WM, et al. Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122–37.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lingen MW, et al. Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas. Oral Oncol. 2013;49(1):1–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.CrossRefGoogle Scholar
  16. 16.
    Chaturvedi AK, et al. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612–9.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kang H, Kiess A, Chung CH. Emerging biomarkers in head and neck cancer in the era of genomics. Nat Rev Clin Oncol. 2015;12(1):11–26.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Califano J, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res. 1996;56(11):2488–92.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Beck TN, Golemis EA. Genomic insights into head and neck cancer. Cancer Head Neck. 2016;1(1):1.CrossRefGoogle Scholar
  20. 20.
    Li H, et al. Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection. Mol Cancer Res. 2014;12(4):571–82.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fertig EJ, et al. Preferential activation of the hedgehog pathway by epigenetic modulations in HPV negative HNSCC identified with meta-pathway analysis. PLoS One. 2013;8(11):e78127.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Gaykalova DA, et al. NF-kappaB and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma. Int J Cancer. 2015;137(8):1879–89.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Rathi KS, et al. Correcting transcription factor gene sets for copy number and promoter methylation variations. Drug Dev Res. 2014;75(6):343–7.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sun W, et al. Activation of the NOTCH pathway in head and neck cancer. Cancer Res. 2014;74(4):1091–104.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Agrawal N, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333(6046):1154–7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Keck MK, et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res. 2015;21(4):870–81.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Guo T, et al. Characterization of functionally active gene fusions in human papillomavirus related oropharyngeal squamous cell carcinoma. Int J Cancer. 2016;139(2):373–82.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Seiwert TY, et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res. 2015;21(3):632–41.CrossRefPubMedGoogle Scholar
  30. 30.
    Han J, et al. Identification of potential therapeutic targets in human head & neck squamous cell carcinoma. Head Neck Oncol. 2009;1:27.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Reddy RB, et al. Meta-analyses of microarray datasets identifies ANO1 and FADD as prognostic markers of head and neck cancer. PLoS One. 2016;11(1):e0147409.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    De Cecco L, et al. Comprehensive gene expression meta-analysis of head and neck squamous cell carcinoma microarray data defines a robust survival predictor. Ann Oncol. 2014;25(8):1628–35.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Schmitz S, et al. Cetuximab promotes epithelial to mesenchymal transition and cancer associated fibroblasts in patients with head and neck cancer. Oncotarget. 2015;6(33):34288–99.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bossi P, et al. Functional genomics uncover the biology behind the responsiveness of head and neck squamous cell cancer patients to cetuximab. Clin Cancer Res. 2016;22(15):3961–70.CrossRefPubMedGoogle Scholar
  35. 35.
    Morris LG, et al. The molecular landscape of recurrent and metastatic head and neck cancers: insights from a precision oncology sequencing platform. JAMA Oncol. 2016;3:244–255.Google Scholar
  36. 36.
    Hedberg ML, et al. Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma. J Clin Invest. 2016;126(1):169–80.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Roepman P, et al. Maintenance of head and neck tumor gene expression profiles upon lymph node metastasis. Cancer Res. 2006;66(23):11110–4.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Colella S, et al. Molecular signatures of metastasis in head and neck cancer. Head Neck. 2008;30(10):1273–83.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Puram SV, et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. In: Cell, vol. 171; 2017. p. 1611.Google Scholar
  40. 40.
    Cheng H, et al. Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma. Cancer Biol Ther. 2015;16(8):1252–8.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Fertig EJ, et al. CoGAPS matrix factorization algorithm identifies transcriptional changes in AP-2alpha target genes in feedback from therapeutic inhibition of the EGFR network. Oncotarget. 2016;7(45):73845–64.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Barretina J, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483(7391):603–307.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Iorio F, et al. A landscape of pharmacogenomic interactions in Cancer. Cell. 2016;166(3):740–54.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Gaykalova DA, et al. Novel insight into mutational landscape of head and neck squamous cell carcinoma. PLoS One. 2014;9(3):e93102.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Xu CC, et al. HPV status and second primary tumours in oropharyngeal squamous cell carcinoma. J Otolaryngol Head Neck Surg. 2013;42:36.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Diaz DA, et al. Head and neck second primary cancer rates in the human papillomavirus era: a population-based analysis. Head Neck. 2016;38 Suppl 1:E873–83.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Henderson S, Fenton T. APOBEC3 genes: retroviral restriction factors to cancer drivers. Trends Mol Med. 2015;21(5):274–84.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Supek F, Lehner B. Clustered mutation signatures reveal that error-prone DNA repair targets mutations to active genes. Cell. 2017;170(3):534–547 e23.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Cancer Genome Atlas Research Network, et al. Integrated genomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378–84.CrossRefGoogle Scholar
  50. 50.
    Hoadley KA, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014;158(4):929–44.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Alexandrov LB, et al. Mutational signatures associated with tobacco smoking in human cancer. Science. 2016;354(6312):618–22.CrossRefPubMedGoogle Scholar
  52. 52.
    Pleasance ED, et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 2010;463(7278):184–90.CrossRefPubMedGoogle Scholar
  53. 53.
    The Cancer Genome Atlas Research Network. Integrated genomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378–84.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hayes DN, Van Waes C, Seiwert TY. Genetic landscape of human papillomavirus-associated head and neck cancer and comparison to tobacco-related tumors. J Clin Oncol. 2015;33(29):3227–34.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Henderson S, et al. APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Rep. 2014;7(6):1833–41.CrossRefPubMedGoogle Scholar
  56. 56.
    Scheffner M, et al. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990;63(6):1129–36.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Boyer SN, Wazer DE, Band V. E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res. 1996;56(20):4620–4.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Sherman L, et al. Inhibition of serum- and calcium-induced differentiation of human keratinocytes by HPV16 E6 oncoprotein: role of p53 inactivation. Virology. 1997;237(2):296–306.CrossRefPubMedGoogle Scholar
  59. 59.
    Guirimand T, Delmotte S, Navratil V. VirHostNet 2.0: surfing on the web of virus/host molecular interactions data. Nucleic Acids Res. 2015;43(Database issue):D583–7.CrossRefPubMedGoogle Scholar
  60. 60.
    Roberts SA, et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet. 2013;45(9):970–6.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Springer S, et al. A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology. 2015;149(6):1501–10.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Vogelstein B, et al. Cancer genome landscapes. Science. 2013;339(6127):1546–58.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Razin A, Riggs AD. DNA methylation and gene function. Science. 1980;210(4470):604–10.CrossRefPubMedGoogle Scholar
  64. 64.
    Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27–36.CrossRefPubMedGoogle Scholar
  65. 65.
    Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8(4):286–98.CrossRefPubMedGoogle Scholar
  66. 66.
    Pikor L, et al. The detection and implication of genome instability in cancer. Cancer Metastasis Rev. 2013;32(3–4):341–52.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Sartor MA, et al. Genome-wide methylation and expression differences in HPV(+) and HPV(−) squamous cell carcinoma cell lines are consistent with divergent mechanisms of carcinogenesis. Epigenetics. 2011;6(6):777–87.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Poage GM, et al. Global hypomethylation identifies Loci targeted for hypermethylation in head and neck cancer. Clin Cancer Res. 2011;17(11):3579–89.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Smith IM, et al. DNA global hypomethylation in squamous cell head and neck cancer associated with smoking, alcohol consumption and stage. Int J Cancer. 2007;121(8):1724–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Hennessey PT, et al. Promoter methylation in head and neck squamous cell carcinoma cell lines is significantly different than methylation in primary tumors and xenografts. PLoS One. 2011;6(5):e20584.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Baylin SB, Jones PA. Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol. 2016;8(9)Google Scholar
  72. 72.
    Kostareli E, et al. HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas. J Clin Invest. 2013;123(6):2488–501.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Ha PK, Califano JA. Promoter methylation and inactivation of tumour-suppressor genes in oral squamous-cell carcinoma. Lancet Oncol. 2006;7(1):77–82.CrossRefPubMedGoogle Scholar
  74. 74.
    Gaykalova DA, et al. Outlier analysis defines zinc finger gene family DNA methylation in tumors and saliva of head and neck cancer patients. PLoS One. 2015;10(11):e0142148.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Worsham MJ, et al. Epigenetic modulation of signal transduction pathways in HPV-associated HNSCC. Otolaryngol Head Neck Surg. 2013;149(3):409–16.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Lleras RA, et al. Unique DNA methylation loci distinguish anatomic site and HPV status in head and neck squamous cell carcinoma. Clin Cancer Res. 2013;19(19):5444–55.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Colacino JA, et al. Comprehensive analysis of DNA methylation in head and neck squamous cell carcinoma indicates differences by survival and clinicopathologic characteristics. PLoS One. 2013;8(1):e54742.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Papillon-Cavanagh S, et al. Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nat Genet. 2017;49(2):180–5.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Brennan K, et al. Identification of an atypical etiological head and neck squamous carcinoma subtype featuring the CpG island methylator phenotype. EBioMedicine. 2017;17:223–36.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Stansfield JC, et al. Toward signaling-driven biomarkers immune to normal tissue contamination. Cancer Inform. 2016;15:15–21.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Gaykalova DA, et al. Integrative computational analysis of transcriptional and epigenetic alterations implicates DTX1 as a putative tumor suppressor gene in HNSCC. Oncotarget. 2017;8:15349.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Maher CA, et al. Transcriptome sequencing to detect gene fusions in cancer. Nature. 2009;458(7234):97–101.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Singh D, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science. 2012;337(6099):1231–5.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Wang R, et al. FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non-small cell lung cancer. Clin Cancer Res. 2014;20(15):4107–14.CrossRefPubMedGoogle Scholar
  85. 85.
    Acquaviva J, et al. FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism. Mol Cancer Res. 2014;12(7):1042–54.CrossRefPubMedGoogle Scholar
  86. 86.
    Wang K, et al. MapSplice: accurate mapping of RNA-seq reads for splice junction discovery. Nucleic Acids Res. 2010;38(18):e178.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Stransky N, et al. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Wu YM, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3(6):636–47.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Daly C, et al. FGFR3-TACC3 fusion proteins act as naturally occurring drivers of tumor resistance by functionally substituting for EGFR/ERK signaling. Oncogene. 2017;36(4):471–81.CrossRefPubMedGoogle Scholar
  90. 90.
    Majewski IJ, et al. Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing. J Pathol. 2013;230(3):270–6.CrossRefPubMedGoogle Scholar
  91. 91.
    Di Stefano AL, et al. Detection, characterization, and inhibition of FGFR-TACC fusions in IDH wild-type glioma. Clin Cancer Res. 2015;21(14):3307–17.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Helsten T, et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016;22(1):259–67.CrossRefPubMedGoogle Scholar
  93. 93.
    Costa R, et al. FGFR3-TACC3 fusion in solid tumors: mini review. Oncotarget. 2016;7(34):55924–38.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Yuan L, et al. Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma. Cancer Biol Ther. 2014;15(12):1613–21.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Nelson KN, et al. Oncogenic gene fusion FGFR3-TACC3 is regulated by tyrosine phosphorylation. Mol Cancer Res. 2016;14(5):458–69.CrossRefPubMedGoogle Scholar
  96. 96.
    Cheng Y, et al. A novel read-through transcript JMJD7-PLA2G4B regulates head and neck squamous cell carcinoma cell proliferation and survival. Oncotarget. 2017;8(2):1972–82.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Rocco JW, et al. p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell. 2006;9(1):45–56.CrossRefPubMedGoogle Scholar
  98. 98.
    Liggett WH Jr, et al. p16 and p16 beta are potent growth suppressors of head and neck squamous carcinoma cells in vitro. Cancer Res. 1996;56(18):4119–23.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Li R, et al. Expression microarray analysis reveals alternative splicing of LAMA3 and DST genes in head and neck squamous cell carcinoma. PLoS One. 2014;9(3):e91263.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Afsari B, et al. Splice Expression Variation Analysis (SEVA) for differential gene isoform usage in cancer. bioRxiv. 2016.  https://doi.org/10.1101/091637.
  101. 101.
    Song L, Sabunciyan S, Florea L. CLASS2: accurate and efficient splice variant annotation from RNA-seq reads. Nucleic Acids Res. 2016;44(10):e98.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Reis EM, et al. Large-scale transcriptome analyses reveal new genetic marker candidates of head, neck, and thyroid cancer. Cancer Res. 2005;65(5):1693–9.CrossRefPubMedGoogle Scholar
  103. 103.
    Chen P, et al. Comprehensive exon array data processing method for quantitative analysis of alternative spliced variants. Nucleic Acids Res. 2011;39(18):e123.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Muller M, et al. One, two, three – p53, p63, p73 and chemosensitivity. Drug Resist Updat. 2006;9(6):288–306.CrossRefPubMedGoogle Scholar
  105. 105.
    Mao L, et al. Frequent abnormalities of FHIT, a candidate tumor suppressor gene, in head and neck cancer cell lines. Cancer Res. 1996;56(22):5128–31.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Frost GI, et al. HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA. Oncogene. 2000;19(7):870–7.CrossRefPubMedGoogle Scholar
  107. 107.
    Cengiz B, et al. Tumor-specific mutation and downregulation of ING5 detected in oral squamous cell carcinoma. Int J Cancer. 2010;127(9):2088–94.CrossRefPubMedGoogle Scholar
  108. 108.
    Richter TM, Tong BD, Scholnick SB. Epigenetic inactivation and aberrant transcription of CSMD1 in squamous cell carcinoma cell lines. Cancer Cell Int. 2005;5:29.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Assimakopoulos D, et al. The role of CD44 in the development and prognosis of head and neck squamous cell carcinomas. Histol Histopathol. 2002;17(4):1269–81.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Guo T, et al. A novel functional splice variant of AKT3 defined by analysis of alternative splice expression in HPV-positive oropharyngeal cancers. Cancer Res. 2017;77(19):5248–58.CrossRefPubMedGoogle Scholar
  111. 111.
    Moller-Levet CS, et al. Exon array analysis of head and neck cancers identifies a hypoxia related splice variant of LAMA3 associated with a poor prognosis. PLoS Comput Biol. 2009;5(11):e1000571.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Sebestyen E, Zawisza M, Eyras E. Detection of recurrent alternative splicing switches in tumor samples reveals novel signatures of cancer. Nucleic Acids Res. 2015;43(3):1345–56.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Radhakrishnan A, et al. Dysregulation of splicing proteins in head and neck squamous cell carcinoma. Cancer Biol Ther. 2016;17(2):219–29.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Ishii H, et al. Epithelial splicing regulatory proteins 1 (ESRP1) and 2 (ESRP2) suppress cancer cell motility via different mechanisms. J Biol Chem. 2014;289(40):27386–99.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Peiqi L, et al. Expression of SRSF3 is correlated with carcinogenesis and progression of oral squamous cell carcinoma. Int J Med Sci. 2016;13(7):533–9.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    House RP, et al. RNA-binding protein CELF1 promotes tumor growth and alters gene expression in oral squamous cell carcinoma. Oncotarget. 2015;6(41):43620–34.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Veneziano D, et al. Noncoding RNA: current deep sequencing data analysis approaches and challenges. Hum Mutat. 2016;37(12):1283–98.CrossRefPubMedGoogle Scholar
  118. 118.
    Guil S, Esteller M. RNA-RNA interactions in gene regulation: the coding and noncoding players. Trends Biochem Sci. 2015;40(5):248–56.CrossRefPubMedGoogle Scholar
  119. 119.
    Ma X, et al. LncRNAs as an intermediate in HPV16 promoting myeloid-derived suppressor cell recruitment of head and neck squamous cell carcinoma. Oncotarget. 2017;8(26):42061–75.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Cao W, et al. A three-lncRNA signature derived from the Atlas of ncRNA in cancer (TANRIC) database predicts the survival of patients with head and neck squamous cell carcinoma. Oral Oncol. 2017;65:94–101.CrossRefPubMedGoogle Scholar
  121. 121.
    Zou AE, et al. The non-coding landscape of head and neck squamous cell carcinoma. Oncotarget. 2016;7(32):51211–22.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Garzon R, et al. MicroRNA expression and function in cancer. Trends Mol Med. 2006;12(12):580–7.CrossRefPubMedGoogle Scholar
  123. 123.
    Guo Z, et al. Genome-wide survey of tissue-specific microRNA and transcription factor regulatory networks in 12 tissues. Sci Rep. 2014;4:5150.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Chang SS, et al. MicroRNA alterations in head and neck squamous cell carcinoma. Int J Cancer. 2008;123(12):2791–7.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Hedback N, et al. MiR-21 expression in the tumor stroma of oral squamous cell carcinoma: an independent biomarker of disease free survival. PLoS One. 2014;9(4):e95193.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Harris T, et al. Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. Am J Pathol. 2012;180(3):917–28.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Avissar M, et al. MicroRNA expression ratio is predictive of head and neck squamous cell carcinoma. Clin Cancer Res. 2009;15(8):2850–5.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Kita Y, et al. Epigenetically regulated microRNAs and their prospect in cancer diagnosis. Expert Rev Mol Diagn. 2014;14(6):673–83.CrossRefPubMedGoogle Scholar
  129. 129.
    Yu L, et al. miR-26a inhibits invasion and metastasis of nasopharyngeal cancer by targeting EZH2. Oncol Lett. 2013;5(4):1223–8.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Kalinowski FC, et al. Regulation of epidermal growth factor receptor signaling and erlotinib sensitivity in head and neck cancer cells by miR-7. PLoS One. 2012;7(10):e47067.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Lu ZM, et al. Micro-ribonucleic acid expression profiling and bioinformatic target gene analyses in laryngeal carcinoma. Onco Targets Ther. 2014;7:525–33.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Howard J, et al. miRNA array analysis determines miR-205 is overexpressed in head and neck squamous cell carcinoma and enhances cellular proliferation. J Cancer Res Ther. 2013;1:153–62.CrossRefGoogle Scholar
  133. 133.
    Miller DL, et al. Identification of a human papillomavirus-associated oncogenic miRNA panel in human oropharyngeal squamous cell carcinoma validated by bioinformatics analysis of the Cancer Genome Atlas. Am J Pathol. 2015;185(3):679–92.CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Lajer CB, et al. The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer. Br J Cancer. 2012;106(9):1526–34.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66.CrossRefPubMedGoogle Scholar
  136. 136.
    Jia LF, et al. Expression, regulation and roles of miR-26a and MEG3 in tongue squamous cell carcinoma. Int J Cancer. 2014;135(10):2282–93.CrossRefPubMedGoogle Scholar
  137. 137.
    Fang Z, et al. Increased expression of the long non-coding RNA UCA1 in tongue squamous cell carcinomas: a possible correlation with cancer metastasis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117(1):89–95.CrossRefPubMedGoogle Scholar
  138. 138.
    Matsui M, Corey DR. Non-coding RNAs as drug targets. Nat Rev Drug Discov. 2017;16(3):167–79.CrossRefPubMedGoogle Scholar
  139. 139.
    Chung CH, et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell. 2004;5(5):489–500.CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Walter V, et al. Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes. PLoS One. 2013;8(2):e56823.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Zhang Y, et al. Subtypes of HPV-positive head and neck cancers are associated with HPV characteristics, copy number alterations, PIK3CA mutation, and pathway signatures. Clin Cancer Res. 2016;22(18):4735–45.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Kelley DZ, et al. Integrated analysis of whole-genome ChIP-Seq and RNA-Seq data of primary head and neck tumor samples associates HPV integration sites with open chromatin marks. Cancer Res. 2017;77:6538.CrossRefPubMedGoogle Scholar
  143. 143.
    Gevaert O, Tibshirani R, Plevritis SK. Pancancer analysis of DNA methylation-driven genes using MethylMix. Genome Biol. 2015;16(1):17.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Parfenov M, et al. Characterization of HPV and host genome interactions in primary head and neck cancers. Proc Natl Acad Sci U S A. 2014;111(43):15544–9.CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Guo T, et al. A novel functional splice variant of AKT3 defined by analysis of alternative splice expression in HPV-positive oropharyngeal cancers. Cancer Res. 2017;77(19):5248–58.CrossRefPubMedGoogle Scholar
  146. 146.
    Olthof NC, et al. Comprehensive analysis of HPV16 integration in OSCC reveals no significant impact of physical status on viral oncogene and virally disrupted human gene expression. PLoS One. 2014;9(2):e88718.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Hajek M, et al. TRAF3/CYLD mutations identify a distinct subset of human papillomavirus-associated head and neck squamous cell carcinoma. Cancer. 2017;123(10):1778–90.Google Scholar
  148. 148.
    Nulton TJ, et al. Analysis of The Cancer Genome Atlas sequencing data reveals novel properties of the human papillomavirus 16 genome in head and neck squamous cell carcinoma. Oncotarget. 2017;8(11):17684–99.Google Scholar
  149. 149.
    Hajek M, et al. TRAF3/CYLD mutations identify a distinct subset of human papilloma virus-associated head and neck squamous cell carcinoma. Cancer. 2017;123:1778.Google Scholar
  150. 150.
    Koneva LA, et al. HPV integration in HNSCC correlates with survival outcomes, immune response signatures, and candidate drivers. Mol Cancer Res. 2017;Google Scholar
  151. 151.
    Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.Google Scholar
  152. 152.
    Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805(1):105–17.Google Scholar
  153. 153.
    Marusyk A, Almendro V, Polyak K. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer. 2012;12(5):323–34.Google Scholar
  154. 154.
    Mroz EA, et al. Intra-tumor genetic heterogeneity and mortality in head and neck cancer: analysis of data from the Cancer Genome Atlas. PLoS Med. 2015;12(2):e1001786.Google Scholar
  155. 155.
    Greaves M, Maley CC. Clonal evolution in cancer. Nature. 2012;481(7381):306–13.Google Scholar
  156. 156.
    Sok JC, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res. 2006;12(17):5064–73.Google Scholar
  157. 157.
    Rocco JW. Mutant Allele Tumor Heterogeneity (MATH) and head and neck squamous cell carcinoma. Head Neck Pathol. 2015;9(1):1–5.Google Scholar
  158. 158.
    Afsari B, Geman D, Fertig EJ. Learning dysregulated pathways in cancers from differential variability analysis. Cancer Inform. 2014;13(Suppl 5):61–7.Google Scholar
  159. 159.
    Eddy JA, et al. Identifying tightly regulated and variably expressed networks by Differential Rank Conservation (DIRAC). PLoS Comput Biol. 2010;6(5):e1000792.Google Scholar
  160. 160.
    Subramanian A, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50.Google Scholar
  161. 161.
    Mroz EA, Rocco JW. MATH, a novel measure of intratumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma. Oral Oncol. 2013;49(3):211–5.Google Scholar
  162. 162.
    Xu Y, et al. MAD bayes for tumor heterogeneity – feature allocation with exponential family sampling. J Am Stat Assoc. 2015;110(510):503–14.Google Scholar
  163. 163.
    Roth A, et al. PyClone: statistical inference of clonal population structure in cancer. Nat Methods. 2014;11(4):396–8.Google Scholar
  164. 164.
    Hackl H, et al. Computational genomics tools for dissecting tumour-immune cell interactions. Nat Rev Genet. 2016;17(8):441–58.Google Scholar
  165. 165.
    Mandal R, et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight. 2016;1(17):e89829.Google Scholar
  166. 166.
    Badoual C, et al. PD-1–expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck Cancer. Cancer Res. 2013;73(1):128.Google Scholar
  167. 167.
    Ferris RL, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–67.Google Scholar
  168. 168.
    Calis JJ, Rosenberg BR. Characterizing immune repertoires by high throughput sequencing: strategies and applications. Trends Immunol. 2014;35(12):581–90.Google Scholar
  169. 169.
    Kelly JR, Husain ZA, Burtness B. Treatment de-intensification strategies for head and neck cancer. Eur J Cancer. 2016;68:125–33.Google Scholar
  170. 170.
    Adelstein DJ, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21(1):92–8.Google Scholar
  171. 171.
    Bonner JA, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78.Google Scholar
  172. 172.
    Seiwert TY, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956–65.Google Scholar
  173. 173.
    Mehra R, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): pooled analyses after long-term follow-up in KEYNOTE-012. In ASCO Annual Meeting. J Clin Oncol. 2016;34Google Scholar
  174. 174.
    Ferris RL. Immunology and immunotherapy of head and neck cancer. J Clin Oncol. 2015;33(29):3293–304.Google Scholar
  175. 175.
    Le DT, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.Google Scholar
  176. 176.
    McGranahan N, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–9.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Farhoud Faraji
    • 1
  • Adrian D. Schubert
    • 1
  • Luciane T. Kagohara
    • 2
  • Marietta Tan
    • 1
  • Yanxun Xu
    • 3
  • Munfarid Zaidi
    • 1
  • Jean-Philippe Fortin
    • 4
  • Carole Fakhry
    • 1
  • Evgeny Izumchenko
    • 1
  • Daria A. Gaykalova
    • 1
  • Elana J. Fertig
    • 2
  1. 1.Department of Otolaryngology-Head and Neck SurgeryJohns Hopkins School of MedicineBaltimoreUSA
  2. 2.Department of Oncology and Division of Biostatistics and BioinformaticsSidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of MedicineBaltimoreUSA
  3. 3.Department of Applied Mathematics and StatisticsWhiting School of Engineering, Johns Hopkins UniversityBaltimoreUSA
  4. 4.Department of Biostatistics, Epidemiology, and InformaticsPerelman School of Medicine, University of PennsylvaniaPhiladelphiaUSA

Personalised recommendations