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03-06-2016 | Head and neck cancers | Article

Genomic insights into head and neck cancer

Journal: Cancers of the Head & Neck

Authors: Tim N. Beck, Erica A. Golemis

Publisher: BioMed Central

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is frequently impervious to curative treatment efforts. Similar to other cancers associated with prolonged exposure to carcinogens, HNSCCs often have a high burden of mutations, contributing to substantial inter- and intra-tumor heterogeneity. The heterogeneity of this malignancy is further increased by the rising rate of human papillomavirus (HPV)-associated (HPV+) HNSCC, which defines an etiological subtype significantly different from the more common tobacco and alcohol associated HPV-negative (HPV-) HNSCC. Since 2011, application of large scale genome sequencing projects by The Cancer Genome Atlas (TCGA) network and other groups have established extensive datasets to characterize HPV- and HPV+ HNSCC, providing a foundation for advanced molecular diagnoses, identification of potential biomarkers, and therapeutic insights. Some genomic lesions are now appreciated as widely dispersed. For example, HPV- HNSCC characteristically inactivates the cell cycle suppressors TP53 (p53) and CDKN2A (p16), and often amplifies CCND1 (cyclin D), which phosphorylates RB1 to promote cell cycle progression from G1 to S. By contrast, HPV+ HNSCC expresses viral oncogenes E6 and E7, which inhibit TP53 and RB1, and activates the cell cycle regulator E2F1. Frequent activating mutations in PIK3CA and inactivating mutations in NOTCH1 are seen in both subtypes of HNSCC, emphasizing the importance of these pathways. Studies of large patient cohorts have also begun to identify less common genetic alterations, predominantly found in HPV- tumors, which suggest new mechanisms relevant to disease pathogenesis. Targets of these alterations including AJUBA and FAT1, both involved in the regulation of NOTCH/CTNNB1 signaling. Genes involved in oxidative stress, particularly CUL3, KEAP1 and NFE2L2, strongly associated with smoking, have also been identified, and are less well understood mechanistically. Application of sophisticated data-mining approaches, integrating genomic information with profiles of tumor methylation and gene expression, have helped to further yield insights, and in some cases suggest additional approaches to stratify patients for clinical treatment. We here discuss some recent insights built on TCGA and other genomic foundations.
Literature
1.
Pfister DG, Spencer S, Brizel DM, Burtness B, Busse PM, Caudell JJ, Cmelak AJ, Colevas AD, Dunphy F, Eisele DW et al. Head and Neck Cancers, Version 1.2015 Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2015;13(7):847–56.PubMed
2.
Burtness B, Golemis EA. Overview: the pathobiology of head and neck cancer. In: Burtness B, Golemis EA, editors. Molecular determinants of head and neck cancer. 1st ed. New York: Springer New York; 2014. p. 1–5.CrossRef
3.
Dillon MT, Harrington KJ. Human papillomavirus-negative pharyngeal cancer. J Clin Oncol. 2015;33(29):3251–61.PubMedCrossRef
4.
Chaturvedi AK, Anderson WF, Lortet-Tieulent J, Curado MP, Ferlay J, Franceschi S, Rosenberg PS, Bray F, Gillison ML. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol. 2013;31(36):4550–9.PubMedPubMedCentralCrossRef
5.
Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. J Clin Oncol. 2015;33(29):3235–42.PubMedCrossRef
6.
Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP, Dal Maso L, Daudt AW, Fabianova E, Fernandez L et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst. 2007;99(10):777–89.PubMedCrossRef
7.
Mehanna H, Beech T, Nicholson T, El-Hariry I, McConkey C, Paleri V, Roberts S. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer--systematic review and meta-analysis of trends by time and region. Head Neck. 2013;35(5):747–55.PubMedCrossRef
8.
Chung CH, Bagheri A, D’Souza G. Epidemiology of oral human papillomavirus infection. Oral Oncol. 2014;50(5):364–9.PubMedPubMedCentralCrossRef
9.
Maxwell JH, Grandis JR, Ferris RL. HPV-Associated Head and Neck Cancer: unique features of epidemiology and clinical management. Annu Rev Med. 2016;67:91–101.
10.
Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C et al. Human papillomavirus and survival of patients with oropharyngeal cancer. New Engl J Med. 2010;363(1):24–35.PubMedPubMedCentralCrossRef
11.
Ang KK, Chen A, Curran Jr WJ, Garden AS, Harari PM, Murphy BA, et al. Head and neck carcinoma in the United States: first comprehensive report of the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN). Cancer. 2012;118(23):5783–92.
12.
Ferris RL. Immunology and immunotherapy of head and neck cancer. J Clin Oncol. 2015;33(29):3293–304.PubMedCrossRef
13.
Huang SH, Xu W, Waldron J, Siu L, Shen X, Tong L, Ringash J, Bayley A, Kim J, Hope A et al. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM stage and prognostic groups for human papillomavirus-related oropharyngeal carcinomas. J Clin Oncol. 2015;33(8):836–45.PubMedCrossRef
14.
O’Rorke MA, Ellison MV, Murray LJ, Moran M, James J, Anderson LA. Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol. 2012;48(12):1191–201.PubMedCrossRef
15.
Garraway LA, Lander ES. Lessons from the cancer genome. Cell. 2013;153(1):17–37.PubMedCrossRef
16.
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546–58.PubMedPubMedCentralCrossRef
17.
Cancer Genome Atlas Research N, Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 2013;45(10):1113–20.CrossRef
18.
Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, Leiserson MDM, Niu BF, McLellan MD, Uzunangelov V et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014;158(4):929–44.PubMedPubMedCentralCrossRef
19.
Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.CrossRef
20.
Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333(6046):1154–7.PubMedPubMedCentralCrossRef
21.
Seiwert TY, Zuo ZX, Keck MK, Khattri A, Pedamallu CS, Stricker T, Brown C, Pugh TJ, Stojanov P, Cho J 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.PubMedPubMedCentralCrossRef
22.
Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60.PubMedPubMedCentralCrossRef
23.
Lui VW, Hedberg ML, Li H, Vangara BS, Pendleton K, Zeng Y, Lu Y, Zhang Q, Du Y, Gilbert BR et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 2013;3(7):761–9.PubMedPubMedCentralCrossRef
24.
McGranahan N, Favero F, de Bruin EC, Birkbak NJ, Szallasi Z, Swanton C. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci Transl Med. 2015;7(283):283ra54.
25.
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21.PubMedPubMedCentralCrossRef
26.
Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nat Genet. 2013;45(10):1127–33.PubMedPubMedCentralCrossRef
27.
Bhatia A, Burtness B. Human papillomavirus-associated oropharyngeal cancer: defining risk groups and clinical trials. J Clin Oncol. 2015;33(29):3243–50.PubMedCrossRef
28.
Vokes EE, Agrawal N, Seiwert TY. HPV-Associated Head and Neck Cancer. J Natl Cancer Inst. 2015;107(12):djv344.
29.
Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011;11(1):9–22.PubMedCrossRef
30.
McLaughlin-Drubin ME, Crum CP, Munger K. Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming. Proc Natl Acad Sci U S A. 2011;108(5):2130–5.PubMedPubMedCentralCrossRef
31.
Munger K, Jones DL. Human papillomavirus carcinogenesis: an identity crisis in the retinoblastoma tumor suppressor pathway. J Virol. 2015;89(9):4708–11.PubMedPubMedCentralCrossRef
32.
Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev. 2009;23(10):1171–6.PubMedPubMedCentralCrossRef
33.
Gillison ML, D’Souza G, Westra W, Sugar E, Xiao W, Begum S, Viscidi R. 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.PubMedCrossRef
34.
Parfenov M, Pedamallu CS, Gehlenborg N, Freeman SS, Danilova L, Bristow CA, Lee S, Hadjipanayis AG, Ivanova EV, Wilkerson MD 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.PubMedPubMedCentralCrossRef
35.
Pickering CR, Zhang J, Yoo SY, Bengtsson L, Moorthy S, Neskey DM, Zhao M, Ortega Alves MV, Chang K, Drummond J et al. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov. 2013;3(7):770–81.PubMedCrossRef
36.
Pickering CR, Zhang JX, Neskey DM, Zhao M, Jasser SA, Wang JP, Ward A, Tsai CJ, Alves MVO, Zhou JH et al. Squamous cell carcinoma of the oral tongue in young Non-smokers is genomically similar to tumors in older smokers. Clin Cancer Res. 2014;20(14):3842–8.PubMedPubMedCentralCrossRef
37.
Lin DC, Meng X, Hazawa M, Nagata Y, Varela AM, Xu L, Sato Y, Liu LZ, Ding LW, Sharma A et al. The genomic landscape of nasopharyngeal carcinoma. Nat Genet. 2014;46(8):866–71.PubMedCrossRef
38.
Gao JJ, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun YC, Jacobsen A, Sinha R, Larsson E et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.
39.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.
40.
Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12(4):R41.PubMedPubMedCentralCrossRef
41.
Masuda M, Yamada T. Signaling pathway profiling by reverse-phase protein array for personalized cancer medicine. Biochim Biophys Acta. 2015;1854(6):651–7.PubMedCrossRef
42.
Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets-update. Nucleic Acids Res. 2013;41(D1):D991–5.
43.
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.PubMedCrossRef
44.
Walter V, Yin X, Wilkerson MD, Cabanski CR, Zhao N, Du Y, 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.
45.
Tai SK, Lee JI, Ang KK, El-Naggar AK, Hassan KA, Liu D, et al. Loss of FHIT expression in head and neck squamous cell carcinoma and its potential clinical implication. Clin Cancer Res. 2004;10(16):5554–7.
46.
Ma C, Quesnelle KM, Sparano A, Rao S, Park MS, Cohen MA, et al. Characterization CSMD1 in a large set of primary lung, head and neck, breast and skin cancer tissues. Cancer Biol Ther. 2009;8(10):907–16.
47.
Scholnick SB, Richter TM. The role of CSMD1 in head and neck carcinogenesis. Genes Chromosomes Cancer. 2003;38(3):281–3.
48.
Cancer Genome Atlas Research N. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519–25.CrossRef
49.
Liu Z, Long XB, Chao C, Yan C, Wu QY, Hua SN, Zhang YJ, Wu AB, Fang WY. Knocking down CDK4 mediates the elevation of let-7c suppressing cell growth in nasopharyngeal carcinoma. Bmc Cancer. 2014;14:274.
50.
Liu N, Boohaker RJ, Jiang C, Boohaker JR, Xu B. A radiosensitivity MiRNA signature validated by the TCGA database for head and neck squamous cell carcinomas. Oncotarget. 2015;6(33):34649–57.PubMedPubMedCentral
51.
Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015;15(1):7–24.PubMedPubMedCentralCrossRef
52.
Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.PubMedCrossRef
53.
Elkabets M, Pazarentzos E, Juric D, Sheng Q, Pelossof RA, Brook S, et al. AXL mediates resistance to PI3K alpha inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell. 2015;27(4):533–46.
54.
Samuels Y, Diaz Jr LA, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell. 2005;7(6):561–73.
55.
Halilovic E, She QB, Ye Q, Pagliarini R, Sellers WR, Solit DB, et al. PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling. Cancer Res. 2010;70(17):6804–14.
56.
Beck TN, Kaczmar J, Handorf E, Nikonova A, Dubyk C, Peri S, et al. Phospho-T356RB1 predicts survival in HPV-negative squamous cell carcinoma of the head and neck. Oncotarget. 2015;6(22):18863–74.
57.
Brachmann SM, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, et al. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci U S A. 2009;106(52):22299–304.
58.
Mohan S, Vander Broek R, Shah S, Eytan DF, Pierce ML, Carlson SG, et al. MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and potentiates antitumor effects in Human Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2015;21(17):3946–56.
59.
Herzog A, Bian YS, Vander Broek R, Hall B, Coupar J, Cheng H, et al. PI3K/mTOR Inhibitor PF-04691502 Antitumor Activity Is Enhanced with Induction of Wild-Type TP53 in Human Xenograft and Murine Knockout Models of Head and Neck Cancer. Clin Cancer Res. 2013;19(14):3808–19.
60.
Rodon J, Dienstmann R, Serra V, Tabemero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol. 2013;10(3):143–53.PubMedCrossRef
61.
Dotto GP. Crosstalk of Notch with p53 and p63 in cancer growth control. Nat Rev Cancer. 2009;9(8):587–95.PubMedCrossRef
62.
Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet. 2003;33(3):416–21.
63.
Duan L, Yao J, Wu X, Fan M. Growth suppression induced by Notch1 activation involves Wnt-beta-catenin down-regulation in human tongue carcinoma cells. Biol Cell. 2006;98(8):479–90.PubMedCrossRef
64.
Dotto GP. Notch tumor suppressor function. Oncogene. 2008;27(38):5115–23.PubMedPubMedCentralCrossRef
65.
Okuyama R, Ogawa E, Nagoshi H, Yabuki M, Kurihara A, Terui T, et al. p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity. Oncogene. 2007;26(31):4478–88.
66.
Yang AN, Kaghad M, Wang YM, Gillett E, Fleming MD, Dotsch V, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998;2(3):305–16.
67.
Wu G, Nomoto S, Hoque MO, Dracheva T, Osada M, Lee CC, et al. DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development. Cancer Res. 2003;63(10):2351–7.
68.
Westfall MD, Pietenpol JA. p63: Molecular complexity in development and cancer. Carcinogenesis. 2004;25(6):857–64.PubMedCrossRef
69.
Melino G. p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53. Cell Death Differ. 2011;18(9):1487–99.PubMedPubMedCentralCrossRef
70.
Zangen R, Ratovitski E, Sidransky D. Delta Np63 alpha levels correlate with clinical tumor response to cisplatin. Cell Cycle. 2005;4(10):1313–5.PubMedCrossRef
71.
Riese U, Dahse R, Fiedler W, Theuer C, Koscielny S, Ernst G, et al. Tumor suppressor gene p16 (CDKN2A) mutation status and promoter inactivation in head and neck cancer. Int J Mol Med. 1999;4(1):61–5.
72.
Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54(18):4855–78.PubMed
73.
Burtness B, Bauman JE, Galloway T. Novel targets in HPV-negative head and neck cancer: overcoming resistance to EGFR inhibition. Lancet Oncol. 2013;14(8):e302–9.PubMedCrossRef
74.
Jensen MA, Fukushima M, Davis RW. DMSO and betaine greatly improve amplification of GC-rich constructs in de novo synthesis. PLoS One. 2010;5(6):e11024.PubMedPubMedCentralCrossRef
75.
Kozarewa I, Ning Z, Quail MA, Sanders MJ, Berriman M, Turner DJ. Amplification-free Illumina sequencing-library preparation facilitates improved mapping and assembly of (G + C)-biased genomes. Nat Methods. 2009;6(4):291–5.PubMedPubMedCentralCrossRef
76.
Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med. 2007;357(25):2552–61.
77.
Masica DL, Li S, Douville C, Manola J, Ferris RL, Burtness B, et al. Predicting survival in head and neck squamous cell carcinoma from TP53 mutation. Hum Genet. 2015;134(5):497–507.
78.
Gross AM, Orosco RK, Shen JP, Egloff AM, Carter H, Hofree M, et al. Multi-tiered genomic analysis of head and neck cancer ties TP53 mutation to 3p loss. Nat Genet. 2014;46(9):939–43.
79.
Song Y, Li L, Ou Y, Gao Z, Li E, Li X, et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature. 2014;509(7498):91–5.
80.
Neskey DM, Osman AA, Ow TJ, Katsonis P, McDonald T, Hicks SC, et al. Evolutionary action score of TP53 identifies high-risk mutations associated with decreased survival and increased distant metastases in head and neck cancer. Cancer Res. 2015;75(7):1527–36.
81.
Osman AA, Neskey DM, Katsonis P, Patel AA, Ward AM, Hsu TK, et al. Evolutionary action score of TP53 coding variants is predictive of platinum response in head and neck cancer patients. Cancer Res. 2015;75(7):1205–15.
82.
Katsonis P, Lichtarge O. A formal perturbation equation between genotype and phenotype determines the evolutionary action of protein-coding variations on fitness. Genome Res. 2014;24(12):2050–8.PubMedPubMedCentralCrossRef
83.
Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009;9(10):701–13.PubMed
84.
Lichtarge O, Wilkins A. Evolution: a guide to perturb protein function and networks. Curr Opin Struc Biol. 2010;20(3):351–9.CrossRef
85.
Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81(3):323–30.PubMedCrossRef
86.
Burke JR, Hura GL, Rubin SM. Structures of inactive retinoblastoma protein reveal multiple mechanisms for cell cycle control. Gene Dev. 2012;26(11):1156–66.PubMedPubMedCentralCrossRef
87.
Wong SQ, Li J, Salemi R, Sheppard KE, Do H, Tothill RW, et al. Targeted-capture massively-parallel sequencing enables robust detection of clinically informative mutations from formalin-fixed tumours. Sci Rep. 2013;3:3494.
88.
Demokan S, Chuang A, Suoglu Y, Ulusan M, Yalniz Z, Califano JA, et al. Promoter methylation and loss of p16INK4a gene expression in head and neck cancer. Head Neck-J Sci Spec. 2012;34(10):1470–5.
89.
El-Naggar AK, Lai S, Clayman G, Lee JK, Luna MA, Goepfert H, et al. Methylation, a major mechanism of p16/CDKN2 gene inactivation in head and neck squamous carcinoma. Am J Pathol. 1997;151(6):1767–74.
90.
Reed AL, Califano J, Cairns P, Westra WH, Jones RM, Koch W, et al. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res. 1996;56(16):3630–3.
91.
Ha PK, Califano JA. Promoter methylation and inactivation of tumour-suppressor genes in oral squamous-cell carcinoma. Lancet Oncol. 2006;7(1):77–82.PubMedCrossRef
92.
Chung CH, Zhang Q, Kong CS, Harris J, Fertig EJ, Harari PM, et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol. 2014;32(35):3930–U3212.
93.
Pollock NI, Grandis JR. HER2 as a therapeutic target in head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(3):526–33.PubMedPubMedCentralCrossRef
94.
Quesnelle KM, Grandis JR. Dual kinase inhibition of EGFR and HER2 overcomes resistance to cetuximab in a novel in vivo model of acquired cetuximab resistance. Clin Cancer Res. 2011;17(18):5935–44.PubMedPubMedCentralCrossRef
95.
Ratushny V, Astsaturov I, Burtness BA, Golemis EA, Silverman JS. Targeting EGFR resistance networks in head and neck cancer. Cell Signal. 2009;21(8):1255–68.PubMedPubMedCentralCrossRef
96.
Marshall ME, Hinz TK, Kono SA, Singleton KR, Bichon B, Ware KE, et al. Fibroblast growth factor receptors are components of autocrine signaling networks in head and neck squamous cell carcinoma cells. Clin Cancer Res. 2011;17(15):5016–25.
97.
Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004;5(11):875–85.PubMedCrossRef
98.
Weber CK, Slupsky JR, Herrmann C, Schuler M, Rapp UR, Block C. Mitogenic signaling of Ras is regulated by differential interaction with Raf isozymes. Oncogene. 2000;19(2):169–76.PubMedCrossRef
99.
Logue JS, Morrison DK. Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy. Gene Dev. 2012;26(7):641–50.PubMedPubMedCentralCrossRef
100.
Morris LGT, Kaufman AM, Gong YX, Ramaswami D, Walsh LA, Turcan S, et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet. 2013;45(3):253–61.
101.
Haraguchi K, Ohsugi M, Abe Y, Semba K, Akiyama T, Yamamoto T. Ajuba negatively regulates the Wnt signaling pathway by promoting GSK-3beta-mediated phosphorylation of beta-catenin. Oncogene. 2008;27(3):274–84.PubMedCrossRef
102.
Nikonova AS, Astsaturov I, Serebriiskii IG, Dunbrack RL, Golemis EA. Aurora A kinase (AURKA) in normal and pathological cell division. Cell Mol Life Sci. 2013;70(4):661–87.PubMedPubMedCentralCrossRef
103.
Mehra R, Serebriiskii IG, Burtness B, Astsaturov I, Golemis EA. Aurora kinases in head and neck cancer. Lancet Oncol. 2013;14(10):e425–35.PubMedPubMedCentralCrossRef
104.
Jaramillo MC, Zhang DD. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 2013;27(20):2179–91.PubMedPubMedCentralCrossRef
105.
Cullinan SB, Gordan JD, Jin JO, Harper JW, Diehl JA. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: Oxidative stress sensing by a Cul3-Keap1 ligase. Mol Cell Biol. 2004;24(19):8477–86.PubMedPubMedCentralCrossRef
106.
Qian Z, Zhou T, Gurguis CI, Xu X, Wen Q, Lv J, et al. Nuclear factor, erythroid 2-like 2-associated molecular signature predicts lung cancer survival. Sci Rep. 2015;5:16889.
107.
Hammerman PS, Hayes DN, Grandis JR. Therapeutic insights from genomic studies of head and neck squamous cell carcinomas. Cancer Discov. 2015;5(3):239–44.PubMedPubMedCentralCrossRef
108.
Martinez VD, Vucic EA, Thu KL, Pikor LA, Lam S, Lam WL. Disruption of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex components by multiple genetic mechanisms: association with poor prognosis in head and neck cancer. Head Neck-J Sci Spec. 2015;37(5):727–34.CrossRef
109.
Choschzick M, Tabibzada AM, Gieseking F, Woelber L, Jaenicke F, Sauter G, et al. BIRC2 amplification in squamous cell carcinomas of the uterine cervix. Virchows Arch. 2012;461(2):123–8.
110.
Imoto I, Tsuda H, Hirasawa A, Miura M, Sakamoto M, Hirohashi S, et al. Expression of cIAP1, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy. Cancer Res. 2002;62(17):4860–6.
111.
Imoto I, Yang ZQ, Pimkhaokham A, Tsuda H, Shimada Y, Imamura M, et al. Identification of cIAP1 as a candidate target gene within an amplicon at 11q22 in esophageal squamous cell carcinomas. Cancer Res. 2001;61(18):6629–34.
112.
Phillips AH, Schoeffler AJ, Matsui T, Weiss TM, Blankenship JW, Zobel K, et al. Internal motions prime cIAP1 for rapid activation. Nat Struct Mol Biol. 2014;21(12):1068–74.
113.
Vallabhapurapu S, Matsuzawa A, Zhang WZ, Tseng PH, Keats JJ, Wang HP, et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappa B signaling. Nat Immunol. 2008;9(12):1364–70.
114.
Stanger BZ. Quit your YAPing: a new target for cancer therapy. Gene Dev. 2012;26(12):1263–7.
115.
Jerhammar F, Johansson AC, Ceder R, Welander J, Jansson A, Grafstrom RC, et al. YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer. Oral Oncol. 2014;50(9):832–9.
116.
Zhang JM, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol. 2009;11(12):1444–U1134.
117.
Pattje WJ, Melchers LJ, Slagter-Menkema L, Mastik MF, Schrijvers ML, Gibcus JH, et al. FADD expression is associated with regional and distant metastasis in squamous cell carcinoma of the head and neck. Histopathology. 2013;63(2):263–70.
118.
Lechner M, Frampton GM, Fenton T, Feber A, Palmer G, Jay A, et al. Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors. Genome Med. 2013;5(5):49.
119.
Khoury JD, Tannir NM, Williams MD, Chen YX, Yao H, Zhang JP, et al. Landscape of DNA virus associations across human malignant cancers: analysis of 3775 cases using RNA-Seq. J Virol. 2013;87(16):8916–26.
120.
Wentzensen N, Vinokurova S, Doeberitz MV. Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res. 2004;64(11):3878–84.PubMedCrossRef
121.
Hu Z, Zhu D, Wang W, Li W, Jia W, Zeng X, et al. Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat Genet. 2015;47(2):158–63.
122.
Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10(8):550–60.PubMedCrossRef
123.
Thomas M, Pim D, Banks L. The role of the E6-p53 interaction in the molecular pathogenesis of HPV. Oncogene. 1999;18(53):7690–700.PubMedCrossRef
124.
Huh K, Zhou XB, Hayakawa H, Cho JY, Libermann TA, Jin JP, et al. Human papillomavirus type 16 E7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor. J Virol. 2007;81(18):9737–47.
125.
Dyson N, Howley PM, Munger K, Harlow E. The human papilloma virus-16 E7-oncoprotein is able to bind to the retinoblastoma gene-product. Science. 1989;243(4893):934–7.PubMedCrossRef
126.
Chung CH, Gillison ML. Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications. Clin Cancer Res. 2009;15(22):6758–62.PubMedCrossRef
127.
Singh P, Thomas GE, Gireesh KK, Manna TK. TACC3 protein regulates microtubule nucleation by affecting gamma-tubulin ring complexes. J Biol Chem. 2014;289(46):31719–35.PubMedPubMedCentralCrossRef
128.
Yao R, Kondoh Y, Natsume Y, Yamanaka H, Inoue M, Toki H, et al. A small compound targeting TACC3 revealed its different spatiotemporal contributions for spindle assembly in cancer cells. Oncogene. 2014;33(33):4242–52.
129.
Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, et al. Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma. Science. 2012;337(6099):1231–5.
130.
Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3(6):636–47.
131.
Yuan L, Liu ZH, Lin ZR, Xu LH, Zhong Q, Zeng MS. Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma. Cancer Biol Ther. 2014;15(12):1613–21.PubMedPubMedCentralCrossRef
132.
Hacker H, Tseng PH, Karin M. Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nat Rev Immunol. 2011;11(7):457–68.PubMedCrossRef
133.
Zhang J, Chen H, Yang X, Guven E, Nussinov R, Chen Z, VanWaes C. Defective TRAF3 modulates alternative NF-kB signaling and cytokine expression to promote cancer cell survival in HPV positive head and neck cancer (TUM10P.1049). J Immunol. 2015;194:211.30.
134.
McGranahan N, Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015;27(1):15–26.PubMedCrossRef
135.
Alizadeh AA, Aranda V, Bardelli A, Blanpain C, Bock C, Borowski C, et al. Toward understanding and exploiting tumor heterogeneity. Nat Med. 2015;21(8):846–53.
136.
Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92.
137.
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.PubMedPubMedCentralCrossRef
138.
Mroz EA, Tward AM, Hammon RJ, Ren Y, Rocco JW. 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.
139.
Landau DA, Carter SL, Getz G, Wu CJ. Clonal evolution in hematological malignancies and therapeutic implications. Leukemia. 2014;28(1):34–43.PubMedPubMedCentralCrossRef
140.
Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013;152(4):714–26.
141.
Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25(1):91–101.
142.
Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012;30(5):413–21.
143.
Swanton C, McGranahan N, Starrett GJ, Harris RS. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov. 2015;5(7):704–12.PubMedPubMedCentralCrossRef
144.
Henderson S, Chakravarthy A, Su X, Boshoff C, Fenton TR. APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Rep. 2014;7(6):1833–41.PubMedCrossRef
145.
Zhao L, Vogt PK. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci U S A. 2008;105(7):2652–7.PubMedPubMedCentralCrossRef
146.
Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015;6:10086.
147.
Moldovan GL, D’Andrea AD. How the Fanconi Anemia pathway guards the genome. Annu Rev Genet. 2009;43:223–49.PubMedPubMedCentralCrossRef
148.
Conti MA, Saleh AD, Brinster LR, Cheng H, Chen Z, Cornelius S, et al. Conditional deletion of nonmuscle myosin II-A in mouse tongue epithelium results in squamous cell carcinoma. Sci Rep. 2015;5:14068.
149.
Schramek D, Sendoel A, Segal JP, Beronja S, Heller E, Oristian D, et al. Direct in Vivo RNAi Screen Unveils Myosin IIa as a Tumor Suppressor of Squamous Cell Carcinomas. Science. 2014;343(6168):309–13.
150.
Ma X, Adelstein RS. The role of vertebrate nonmuscle Myosin II in development and human disease. Bioarchitecture. 2014;4(3):88–102.PubMedPubMedCentralCrossRef
151.
Bozic I, Reiter JG, Allen B, Antal T, Chatterjee K, Shah P, et al. Evolutionary dynamics of cancer in response to targeted combination therapy. Elife. 2013;2:e00747.
152.
Mirghani H, Amen F, Blanchard P, Moreau F, Guigay J, Hartl DM, et al. Treatment de-escalation in HPV-positive oropharyngeal carcinoma: ongoing trials, critical issues and perspectives. Int J Cancer. 2015;136(7):1494–503.
153.
Liu H, Cracchiolo JR, Beck TN, Serebriiskii IG, Golemis EA. EGFR inhibitors as therapeutic agents in head and neck cancer. In: Burtness B, Golemis EA, editors. Molecular determinants of head and neck cancer. 1st ed. New York: Springer New York; 2014. p. 55–90.CrossRef
154.
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–27.
155.
Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA, Eastern Cooperative Oncology G. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an eastern cooperative oncology group study. J Clin Oncol. 2005;23(34):8646–54.PubMedCrossRef
156.
Harrington K, Berrier A, Robinson M, Remenar E, Housset M, de Mendoza FH, et al. Randomised Phase II study of oral lapatinib combined with chemoradiotherapy in patients with advanced squamous cell carcinoma of the head and neck: rationale for future randomised trials in human papilloma virus-negative disease. Eur J Cancer. 2013;49(7):1609–18.
157.
Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, et al. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol. 2015;16(5):583–94.
158.
Chong CR, Janne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med. 2013;19(11):1389–400.PubMedPubMedCentralCrossRef
159.
Dorsey K, Agulnik M. Promising new molecular targeted therapies in head and neck cancer. Drugs. 2013;73(4):315–25.PubMedCrossRef
160.
Suh Y, Amelio I, Guerrero Urbano T, Tavassoli M. Clinical update on cancer: molecular oncology of head and neck cancer. Cell Death Dis. 2014;5:e1018.PubMedPubMedCentralCrossRef
161.
Sacco AG, Cohen EE. Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma. J Clin Oncol. 2015;33(29):3305–13.PubMedCrossRef
162.
Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14(2):130–46.PubMedPubMedCentralCrossRef
163.
Shaw AT, Hsu PP, Awad MM, Engelman JA. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer. 2013;13(11):772–87.PubMedPubMedCentralCrossRef
164.
Huang M, Shen AJ, Ding J, Geng MY. Molecularly targeted cancer therapy: some lessons from the past decade. Trends Pharmacol Sci. 2014;35(1):41–50.PubMedCrossRef
165.
Matzinger O, Viertl D, Tsoutsou P, Kadi L, Rigotti S, Zanna C, et al. The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNF alpha-mediated in head and neck squamous cell carcinoma. Radiother Oncol. 2015;116(3):495–503.
166.
Eytan DF, Snow GE, Carlson SG, Schiltz S, Chen Z, Van Waes C. Combination effects of SMAC mimetic birinapant with TNFalpha, TRAIL, and docetaxel in preclinical models of HNSCC. Laryngoscope. 2015;125(3):E118–24.PubMedPubMedCentralCrossRef
167.
Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015;14(8):561–84.PubMedCrossRef
168.
Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2015;33(18):2004–U2032.
169.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39.
170.
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.
171.
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.
172.
Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–82.PubMedCrossRef
173.
Kuss I, Hathaway B, Ferris RL, Gooding W, Whiteside TL. Decreased absolute counts of T lymphocyte subsets and their relation to disease in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2004;10(11):3755–62.PubMedCrossRef
174.
Jie HB, Schuler PJ, Lee SC, Srivastava RM, Argiris A, Ferrone S, et al. CTLA-4(+) regulatory T cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res. 2015;75(11):2200–10.
175.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.PubMedPubMedCentralCrossRef
176.
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.
177.
Garon EB, Rizvi NA, Hui RN, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. New Engl J Med. 2015;372(21):2018–28.
178.
Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–18.
179.
Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084–9.
180.
Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–84.
181.
Weisenberger DJ. Characterizing DNA methylation alterations from the Cancer Genome Atlas. J Clin Invest. 2014;124(1):17–23.PubMedPubMedCentralCrossRef
182.
Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92.PubMedPubMedCentralCrossRef
183.
Lleras RA, Smith RV, Adrien LR, Schlecht NF, Burk RD, Harris TM, 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.
184.
Schlecht NF, Ben-Dayan M, Anayannis N, Lleras RA, Thomas C, Wang Y, et al. Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV-positive oropharyngeal squamous cell carcinoma. Cancer Med. 2015;4(3):342–53.
185.
Gaykalova DA, Vatapalli R, Wei Y, Tsai HL, Wang H, Zhang C, 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.
186.
Timmermann S, Hinds PW, Munger K. Re-expression of endogenous p16(ink4a) in oral squamous cell carcinoma lines by 5-aza-2 '-deoxycytidine treatment induces a senescence-like state. Oncogene. 1998;17(26):3445–53.PubMedCrossRef
187.
Shi H, Chen X, Lu C, Gu CM, Jiang HW, Meng RW, Niu X, Huang YX, Lu MX. Association between P16(INK4a) promoter methylation and HNSCC: a meta-analysis of 21 published studies. Plos One. 2015;10(4):e0122302.
188.
Kostareli E, Holzinger D, Bogatyrova O, Hielscher T, Wichmann G, Keck M, et al. HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas. J Clin Invest. 2013;123(6):2488–501.
189.
Shi H, Chen X, Lu C, Gu C, Jiang H, Meng R, et al. Association between P16INK4a promoter methylation and HNSCC: a meta-analysis of 21 published studies. PLoS One. 2015;10(4):e0122302.
190.
Chen X, Liu L, Mims J, Punska EC, Williams KE, Zhao W, et al. Analysis of DNA methylation and gene expression in radiation-resistant head and neck tumors. Epigenetics. 2015;10(6):545–61.
191.
Le Tourneau C, Kamal M, Tsimberidou AM, Bedard P, Pierron G, Callens C, Rouleau E, Vincent-Salomon A, Servant N, Alt M, et al. Treatment algorithms based on tumor molecular profiling: the essence of precision medicine trials. J Natl Cancer Inst. 2016;108(4):djv362.
192.
Le Tourneau C, Paoletti X, Servant N, Bieche I, Gentien D, Rio Frio T, et al. Randomised proof-of-concept phase II trial comparing targeted therapy based on tumour molecular profiling vs conventional therapy in patients with refractory cancer: results of the feasibility part of the SHIVA trial. Br J Cancer. 2014;111(1):17–24.
193.
Rodon J, Soria JC, Berger R, Batist G, Tsimberidou A, Bresson C, et al. Challenges in initiating and conducting personalized cancer therapy trials: perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium trial. Ann Oncol. 2015;26(8):1791–8.
194.
Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, et al. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 2014;24(5):743–50.
195.
Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.
196.
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33.
197.
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.
198.
Hariri S, Markowitz LE, Dunne EF, Unger ER. Population impact of HPV vaccines: summary of early evidence. J Adolesc Health. 2013;53(6):679–82.PubMedCrossRef
199.
Baldur-Felskov B, Dehlendorff C, Munk C, Kjaer SK. Early impact of human papillomavirus vaccination on cervical neoplasia--nationwide follow-up of young Danish women. J Natl Cancer Inst. 2014;106(3):djt460.PubMedCrossRef