Grundlagen der Tumorentstehung und die Bedeutung Humaner Papillomaviren (HPV) bei Kopf-Hals-Karzinomen

 

 Buy Article Permissions and Reprints

Zusammenfassung

Plattenepithelkarzinome des Kopf-Hals-Bereiches (head and neck squamous cell carcinoma, HNSCC) gehören zu den häufigsten bösartigen Tumorerkrankungen weltweit. Während die Inzidenz von Larynx- und Hypopharynxkarzinomen abnimmt, wird aktuell eine Zunahme bei Oropharynxkarzinomen (oropharyngeal squamous cell carcinoma – OSCC) angenommen. Zigarettenrauchen und Alkoholkonsum sind klassische Risikofaktoren für HNSCC. In den letzten Jahren hat sich gezeigt, dass in einem Prozentsatz zwischen 25 und 60% OSCC mit einer Infektion durch onkogene humane Papillomaviren (HPV) assoziiert sind. Die Entstehung eines Kopf-Hals-Tumors wird normalerweise wesentlich durch Akkumulation genetischer Veränderungen, die zu Inaktivierung von Tumorsuppressorgenen oder Aktivierung von Proto-Onkogenen führen, vorangetrieben. Dabei führt eine mehr oder weniger gleichförmige zeitliche Abfolge von DNA-Schäden zur genetischen Instabilität. Ein häufiges frühes Ereignis ist dabei beispielsweise eine Deletion im kurzen Arm des Chromosoms 9, welche zur Inaktivierung des p16-Gens führt. Bei HPV-induzierter Karzinogene ist dagegen die Expression der viralen Proteine E6 und E7, die zu einer Inaktivierung der zellulären Tumorsuppressorproteine p53 und Rb führen, für die Tumorentstehung entscheidend. Die HPV-Assoziation von HNSCC kann mit in der Routine etablierten Methoden nachgewiesen werden. Der natürliche transorale Infektionsweg ist nicht sicher aufgeklärt. Tatsache ist, dass die perorale HPV-Infektion nicht selten ist, und normalerweise ereignislos abheilt. Rauchen scheint die Wahrscheinlichkeit für die Entwicklung eines HPV-assoziierten Tumors zu begünstigen. Neben bekannten klassischen Prognosefaktoren ist die Aufdeckung einer HPV-Assoziation wegweisend. Die prognostische Relevanz von HPV übersteigt wahrscheinlich viele bekannte Risikofaktoren, beispielsweise eine regionäre Metastasierung. Hierdurch werden sich in Zukunft möglicherweise auch unterschiedliche Therapieansätze für beide Untergruppen von Patienten ergeben. Insbesondere Patienten mit HPV-assoziierten OSCC könnten möglicherweise auch weniger aggressiv erfolgreich behandelt werden. Andere molekulare Marker sind bisher nicht in der Routine etabliert. Abschließend wird im Referat ein Ausblick auf zielgerichtete Therapieansätze gegeben, von denen in der klinischen Praxis bisher lediglich Antikörper gegen den EGF-Rezeptor etabliert sind.

Abstract

Basics of Tumor Development and Importance of Human Papilloma Virus (HPV) for Head and Neck Cancer

Head and Neck Squamous Cell Carcinoma (HNSCC) are the 6th most common cancers worldwide. While the incidence of larynx-hypopharynx carcinoma decreases, actually an increase in oropharyngeal squamous cell carcinoma (OSCC) is observed. Classical risk factors for HNSCC are smoking and alcohol. Though, it was shown recently for 25 to 60% of OSCC, to be associated with an infection by oncogenic human papilloma virus (HPV). The development of “common” head-neck-tumors is substantially enhanced by an accumulation of genetic changes, which lead to an inactivation of tumor suppressor genes or to an activation of proto-oncogenes. A more or less uniform sequence of different DNA-damages leads to genetic instability. In this context, an early and frequent event is deletion on the short arm of chromosome 9, which results in inactivation of the p16-gene. On the contrary, for HPV-induced carcinogenesis, expression of the viral proteins E6 and E7 is most important, since E6 and E7 lead to inactivation of the cellular tumor-suppressor-proteins p53 and Rb. The process of natural transoral infection is not yet clear. However, as a matter of fact peroral HPV-infection is not seldom and in most cases such an infection heals completely and uneventfully. Smoking seems to increases the probability for developing an HPV-associated tumor. The association of HNSCC with HPV can be proven with established methods in clinical diagnostics. In addition to classical prognostic factors, diagnosis of an HPV-association may become important for future therapies. Prognostic relevance of HPV probably surmounts many known risk-factors, for instance regional metastasis. Until now, no other molecular markers are established in clinical routine. Future therapy concepts may vary for the two subgroups of patients, especially patients with HPV-associated OSCC may take advantage of a less aggressive postoperative treatment. Finally an outlook will be given on possible target-aimed therapies, of which so far only antibodies against EGF-receptors are established in clinical practice.

• Literatur

• 1 Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005 55. 74-108
  PubMedGoogle Scholar
• 2 Jemal A, Siegel R, Ward E et al. Cancer statistics, 2007. CA Cancer J Clin. 2007 57. 43-66
  PubMedGoogle Scholar
• 3 Sankaranarayanan R, Masuyer E, Swaminathan R et al. Head and neck cancer: a global perspective on epidemiology and prognosis. Anticancer Res 1998; 18: 4779-4786
  PubMedGoogle Scholar
• 4 Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers?. Cancer 2007; 110: 1429-1435
  CrossrefPubMedGoogle Scholar
• 5 Hammarstedt L, Dahlstrand H, Lindquist D et al. The incidence of tonsillar cancer in Sweden is increasing. Acta Otolaryngol 2007; 127: 988-992
  CrossrefPubMedGoogle Scholar
• 6 Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20–44 years. Cancer 2005; 103: 1843-1849
  CrossrefPubMedGoogle Scholar
• 7 Blomberg M, Nielsen A, Munk C et al. Trends in head and neck cancer incidence in Denmark, 1978–2007: focus on human papillomavirus associated sites. Int J Cancer 2011; 129: 733-741
  CrossrefPubMedGoogle Scholar
• 8 De Souza DL, De Camargo Cancela M, Perez MM et al. Trends in the incidence of oral cavity and oropharyngeal cancers in Spain. Head Neck 2001;
  PubMedGoogle Scholar
• 9 Sturgis EM, Ang KK. The epidemic of HPV-associated oropharyngeal cancer is here: is it time to change our treatment paradigms?. J Natl Compr Canc Netw 2011; 9: 665-673
  PubMedGoogle Scholar
• 10 Mork J, Moller B, Dahl T et al. Time trends in pharyngeal cancer incidence in Norway 1981–2005: a subsite analysis based on a reabstraction and recoding of registered cases. Cancer Causes Control 2010; 21: 1397-1405
  CrossrefPubMedGoogle Scholar
• 11 Chaturvedi AK, Engels EA, Anderson WF et al. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 2008; 26: 612-619
  CrossrefPubMedGoogle Scholar
• 12 Adelstein DJ, Ridge JA, Gillison MI et al. Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9–10, 2008, Washington, D.C. Head Neck 2009; 31: 1393-1422
  CrossrefPubMedGoogle Scholar
• 13 D’souza G, Kreimer AR, Viscidi R et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007; 356: 1944-1956
  CrossrefPubMedGoogle Scholar
• 14 Klussmann JP, Weissenborn SJ, Wieland U et al. Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas. Cancer 2001; 92: 2875-2884
  CrossrefPubMedGoogle Scholar
• 15 D’souza G, Agrawal Y, Halpern J et al. Oral sexual behaviors associated with prevalent oral human papillomavirus infection. J Infect Dis 2009; 199: 1263-1269
  CrossrefPubMedGoogle Scholar
• 16 Loning T, Ikenberg H, Becker J et al. Analysis of oral papillomas, leukoplakias, and invasive carcinomas for human papillomavirus type related DNA. J Invest Dermatol 1985; 84: 417-420
  CrossrefPubMedGoogle Scholar
• 17 Marur S, D’souza G, Westra WH et al. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 2010; 11: 781-789
  CrossrefPubMedGoogle Scholar
• 18 Nasman A, Attner P, Hammarstedt L et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?. Int J Cancer 2009; 125: 362-366
  CrossrefPubMedGoogle Scholar
• 19 Klussmann JP, Dinh S, Guntinas-Lichius O et al. HPV-associated tonsillar cancer. An update. HNO 2004; 52: 208-218
  CrossrefPubMedGoogle Scholar
• 20 Klussmann JP, Preuss SF, Speel EJ. Human papillomavirus and cancer of the oropharynx. Molecular interaction and clinical implications. HNO 2009; 57: 113-122
  CrossrefPubMedGoogle Scholar
• 21 Kreimer AR, Clifford GM, Boyle P et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005; 14: 467-475
  CrossrefPubMedGoogle Scholar
• 22 Ribeiro KB, Levi JE, Pawlita M et al. Low human papillomavirus prevalence in head and neck cancer: results from two large case-control studies in high-incidence regions. Int J Epidemiol 2011; 40: 489-502
  CrossrefPubMedGoogle Scholar
• 23 Kutler DI, Auerbach AD, Satagopan J et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg 2003; 129: 106-112
  CrossrefPubMedGoogle Scholar
• 24 Wynder EL, Bross IJ. Aetiological factors in mouth cancer; an approach to its prevention. Br Med J 1957; 1: 1137-1143
  CrossrefPubMedGoogle Scholar
• 25 Franceschi S, Levi F, La Vecchia C et al. Comparison of the effect of smoking and alcohol drinking between oral and pharyngeal cancer. Int J Cancer 1999; 83: 1-4
  PubMedGoogle Scholar
• 26 Talamini R, Bosetti C, La Vecchia C et al. Combined effect of tobacco and alcohol on laryngeal cancer risk: a case-control study. Cancer Causes Control 2002; 13: 957-964
  CrossrefPubMedGoogle Scholar
• 27 Pai SI, Westra WH. Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment. Annu Rev Pathol 2009; 4: 49-70
  CrossrefPubMedGoogle Scholar
• 28 Llewellyn CD, Linklater K, Bell J et al. Squamous cell carcinoma of the oral cavity in patients aged 45 years and under: a descriptive analysis of 116 cases diagnosed in the South East of England from 1990 to 1997. Oral Oncol. 2003 39. 106-114
  PubMedGoogle Scholar
• 29 Koch WM, Lango M, Sewell D et al. Head and neck cancer in nonsmokers: a distinct clinical and molecular entity. Laryngoscope 1999; 109: 1544-1551
  CrossrefPubMedGoogle Scholar
• 30 Castellsague X, Quintana MJ, Martinez MC et al. The role of type of tobacco and type of alcoholic beverage in oral carcinogenesis. Int J Cancer 2004; 108: 741-749
  CrossrefPubMedGoogle Scholar
• 31 Zhang ZF, Morgenstern H, Spitz MR et al. Environmental tobacco smoking, mutagen sensitivity, and head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 2000; 9: 1043-1049
  PubMedGoogle Scholar
• 32 Schlecht NF, Franco EL, Pintos J et al. Effect of smoking cessation and tobacco type on the risk of cancers of the upper aero-digestive tract in Brazil. Epidemiology 1999; 10: 412-418
  Google Scholar
• 33 Gillison ML, Koch WM, Capone RB. et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000; 92: 709-720
  CrossrefPubMedGoogle Scholar
• 34 Wiest T, Schwarz E, Enders C et al. Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control. Oncogene 2002; 21: 1510-1517
  CrossrefPubMedGoogle Scholar
• 35 Braakhuis BJ, Snijders PJ, Keune WJ et al. Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst 2004; 96: 998-1006
  CrossrefPubMedGoogle Scholar
• 36 Termine N, Giovannelli L, Matranga D et al. Oral human papillomavirus infection in women with cervical HPV infection: new data from an Italian cohort and a metanalysis of the literature. Oral Oncol 2011; 47: 244-250
  CrossrefPubMedGoogle Scholar
• 37 Rintala MA, Grenman SE, Jarvenkyla ME et al. High-risk types of human papillomavirus (HPV) DNA in oral and genital mucosa of infants during their first 3 years of life: experience from the Finnish HPV Family Study. Clin Infect Dis 2005; 41: 1728-1733
  CrossrefPubMedGoogle Scholar
• 38 Do Sacramento PR, Babeto E, Colombo J et al. The prevalence of human papillomavirus in the oropharynx in healthy individuals in a Brazilian population. J Med Virol 2006; 78: 614-618
  CrossrefPubMedGoogle Scholar
• 39 Klingenberg B, Hafkamp HC, Haesevoets A et al. p16 INK4A overexpression is frequently detected in tumour-free tonsil tissue without association with HPV. Histopathology 2010; 56: 957-967
  CrossrefPubMedGoogle Scholar
• 40 Smith EM, Ritchie JM, Summersgill KF et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer 2004; 108: 766-772
  CrossrefPubMedGoogle Scholar
• 41 Kreimer AR, Alberg AJ, Daniel R et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis 2004; 189: 686-698
  CrossrefPubMedGoogle Scholar
• 42 Mork J, Lie AK, Glattre E. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001; 344: 1125-1131
  CrossrefPubMedGoogle Scholar
• 43 Heck JE, Berthiller J, Vaccarella S et al. Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol 2010; 39: 166-181
  CrossrefPubMedGoogle Scholar
• 44 Gillison ML, D’souza G, Westra W 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: 407-420
  CrossrefPubMedGoogle Scholar
• 45 Syrjanen S. The role of human papillomavirus infection in head and neck cancers. Ann Oncol 2010; 21 (Suppl. 07) vii243-vii245
  CrossrefPubMedGoogle Scholar
• 46 Kjaer SK, Engholm G, Dahl C et al. Case-control study of risk factors for cervical squamous cell neoplasia in Denmark. IV: role of smoking habits. Eur J Cancer Prev 1996; 5: 359-365
  CrossrefPubMedGoogle Scholar
• 47 Giuliano AR, Sedjo RL, Roe DJ et al. Clearance of oncogenic human papillomavirus (HPV) infection: effect of smoking (United States). Cancer Causes Control 2002; 13: 839-846
  CrossrefPubMedGoogle Scholar
• 48 Ndisang D, Khan A, Lorenzato F et al. The cellular transcription factor Brn-3a and the smoking-related substance nicotine interact to regulate the activity of the HPV URR in the cervix. Oncogene 2010; 29: 2701-2711
  CrossrefPubMedGoogle Scholar
• 49 Sinha P, Logan HL, Mendenhall WM. Human papillomavirus, smoking, and head and neck cancer. Am J Otolaryngol 2011;
  PubMedGoogle Scholar
• 50 Applebaum KM, Furniss CS, Zeka A et al. Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. J Natl Cancer Inst 2007; 99: 1801-1810
  CrossrefPubMedGoogle Scholar
• 51 Smith EM, Rubenstein LM, Haugen TH et al. Tobacco and alcohol use increases the risk of both HPV-associated and HPV-independent head and neck cancers. Cancer Causes Control 2010; 21: 1369-1378
  CrossrefPubMedGoogle Scholar
• 52 Herrero R, Castellsague X, Pawlita M et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003; 95: 1772-1783
  CrossrefPubMedGoogle Scholar
• 53 Hafkamp HC, Manni JJ, Haesevoets A et al. Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas. Int J Cancer 2008; 122: 2656-2664
  CrossrefPubMedGoogle Scholar
• 54 Albers AE, Hoffmann TK, Klussmann JP et al. Prophylactic and therapeutic vaccines against human papilloma virus. HNO 2010; 58: 778-790
  CrossrefPubMedGoogle Scholar
• 55 Pathirana D, Hillemanns P, Petry KU et al. Short version of the German evidence-based Guidelines for prophylactic vaccination against HPV-associated neoplasia. Vaccine 2009; 27: 4551-4559
  CrossrefPubMedGoogle Scholar
• 56 Robert-Koch-Institut . Impfungen gegen humane Papillomaviren (HPV) für Mädchen und Frauen von 12–17 Jahren – Empfehlung und Begründung. Epid Bull 2007; 12: 7
  PubMedGoogle Scholar
• 57 Robert-Koch-Institut . Impfungen gegen HPV – Aktuelle Bewertung der STIKO. Epid Bull 2009; 32: 9
  PubMedGoogle Scholar
• 58 Hildesheim A, Herrero R, Wacholder S et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA 2007; 298: 743-753
  CrossrefPubMedGoogle Scholar
• 59 Schiller JT, Lowy DR. et al. Prospects for cervical cancer prevention by human papillomavirus vaccination. Cancer Res 2006; 66: 10229-10232
  CrossrefPubMedGoogle Scholar
• 60 Campo MS, Roden RB et al. Papillomavirus prophylactic vaccines: established successes, new approaches. J Virol 2010; 84: 1214-1220
  CrossrefPubMedGoogle Scholar
• 61 Li YL, Qiu XH, Shen C et al. Vaccination of full-length HPV16 E6 or E7 protein inhibits the growth of HPV16 associated tumors. Oncol Rep 2010; 24: 1323-1329
  PubMedGoogle Scholar
• 62 Huang CF, Monie A, Weng WH et al. DNA vaccines for cervical cancer. Am J Transl Res 2010; 2: 75-87
  PubMedGoogle Scholar
• 63 Donovan B, Franklin N, Guy R et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infect Dis 2011; 11: 39-44
  CrossrefPubMedGoogle Scholar
• 64 Giuliano AR, Palefsky JM, Goldstone S et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med 2011; 364: 401-411
  CrossrefPubMedGoogle Scholar
• 65 Michor F, Polyak K. The origins and implications of intratumor heterogeneity. Cancer Prev Res (Phila) 2010; 3: 1361-1364
  CrossrefPubMedGoogle Scholar
• 66 Slebos RJ, Yi Y, Ely K et al. Gene expression differences associated with human papillomavirus status in head and neck squamous cell carcinoma. Clin Cancer Res 2006; 12: 701-709
  CrossrefPubMedGoogle Scholar
• 67 Chung CH, Parker JS, Ely K et al. Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-kappaB signaling as characteristics of a high-risk head and neck squamous cell carcinoma. Cancer Res 2006; 66: 8210-8218
  CrossrefPubMedGoogle Scholar
• 68 Chung CH, Parker JS, Karaca G et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell 2004; 5: 489-500
  CrossrefPubMedGoogle Scholar
• 69 Hermsen M, Guervos MA, Meijer G et al. New chromosomal regions with high-level amplifications in squamous cell carcinomas of the larynx and pharynx, identified by comparative genomic hybridization. J Pathol 2001; 194: 177-182
  CrossrefPubMedGoogle Scholar
• 70 Jin C, Jin Y, Wennerberg J et al. Cytogenetic abnormalities in 106 oral squamous cell carcinomas. Cancer Genet Cytogenet 2006; 164: 44-53
  CrossrefPubMedGoogle Scholar
• 71 Smeets SJ, Brakenhoff RH, Ylstra B et al. Genetic classification of oral and oropharyngeal carcinomas identifies subgroups with a different prognosis. Cell Oncol 2009; 31: 291-300
  PubMedGoogle Scholar
• 72 Klussmann JP, Mooren JJ, Lehnen M et al. Genetic signatures of HPV-related and unrelated oropharyngeal carcinoma and their prognostic implications. Clin Cancer Res 2009; 15: 1779-1786
  CrossrefPubMedGoogle Scholar
• 73 Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6: 963-968
  CrossrefPubMedGoogle Scholar
• 74 Mcgovern SL, Williams MD, Weber RS et al. Three synchronous HPV-associated squamous cell carcinomas of Waldeyer’s ring: case report and comparison with Slaughter’s model of field cancerization. Head Neck 2010; 32: 1118-1124
  PubMedGoogle Scholar
• 75 Mao L, Hong WK, Papadimitrakopoulou VA. Focus on head and neck cancer. Cancer Cell 2004; 5: 311-316
  CrossrefPubMedGoogle Scholar
• 76 Hogmo A, Munck-Wikland E, Kuylenstierna R et al. Nuclear DNA content and p53 immunostaining in metachronous preneoplastic lesions and subsequent carcinomas of the oral cavity. Head Neck 1996; 18: 433-440
  CrossrefPubMedGoogle Scholar
• 77 Sudbo J, Lippman SM, Lee JJ et al. The influence of resection and aneuploidy on mortality in oral leukoplakia. N Engl J Med 2004; 350: 1405-1413
  CrossrefPubMedGoogle Scholar
• 78 Mao L, Lee JS, Fan YH et al. Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nat Med 1996; 2: 682-685
  CrossrefPubMedGoogle Scholar
• 79 Rosin MP, Cheng X, Poh C et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000; 6: 357-362
  PubMedGoogle Scholar
• 80 Izzo JG, Papadimitrakopoulou VA, Liu DD et al. Cyclin D1 genotype, response to biochemoprevention, and progression rate to upper aerodigestive tract cancer. J Natl Cancer Inst 2003; 95: 198-205
  CrossrefPubMedGoogle Scholar
• 81 Mutirangura A, Supiyaphun P, Trirekapan S et al. Telomerase activity in oral leukoplakia and head and neck squamous cell carcinoma. Cancer Res 1996; 56: 3530-3533
  PubMedGoogle Scholar
• 82 Shin DM, Charuruks N, Lippman SM et al. p53 protein accumulation and genomic instability in head and neck multistep tumorigenesis. Cancer Epidemiol Biomarkers Prev 2001; 10: 603-609
  PubMedGoogle Scholar
• 83 Reed AL, Califano J, Cairns P et al. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res 1996; 56: 3630-3633
  PubMedGoogle Scholar
• 84 Smeets SJ, Braakhuis BJ, Abbas S et al. Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus. Oncogene 2006; 25: 2558-2564
  CrossrefPubMedGoogle Scholar
• 85 Smirnova T, Adomako A, Locker J. In vivo invasion of head and neck squamous cell carcinoma cells does not require macrophages. Am J Pathol 2011; 178: 2857-2865
  CrossrefPubMedGoogle Scholar
• 86 Yeudall WA, Miyazaki H, Ensley JF et al. Uncoupling of epidermal growth factor-dependent proliferation and invasion in a model of squamous carcinoma progression. Oral Oncol 2005; 41: 698-708
  CrossrefPubMedGoogle Scholar
• 87 Fei J, Hong A, Dobbins TA et al. Prognostic significance of vascular endothelial growth factor in squamous cell carcinomas of the tonsil in relation to human papillomavirus status and epidermal growth factor receptor. Ann Surg Oncol 2009; 16: 2908-2917
  CrossrefPubMedGoogle Scholar
• 88 Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 2010; 10: 415-424
  CrossrefPubMedGoogle Scholar
• 89 Qiu W, Schonleben F, Li X et al. Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4. Cancer Lett 2007; 245: 163-170
  CrossrefPubMedGoogle Scholar
• 90 Bornstein S, White R, Malkoski S et al. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest 2009; 119: 3408-3419
  PubMedGoogle Scholar
• 91 Cohen J, Chen Z, Lu SL et al. Attenuated transforming growth factor beta signaling promotes nuclear factor-kappaB activation in head and neck cancer. Cancer Res 2009; 69: 3415-3424
  CrossrefPubMedGoogle Scholar
• 92 Nathan CO, Amirghahari N, Abreo F et al. Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/mammalian target of rapamycin pathway. Clin Cancer Res 2004; 10: 5820-5827
  CrossrefPubMedGoogle Scholar
• 93 Pickering BM, Willis AE. The implications of structured 5‘ untranslated regions on translation and disease. Semin Cell Dev Biol 2005; 16: 39-47
  CrossrefPubMedGoogle Scholar
• 94 Okami K, Wu L, Riggins G et al. Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumors. Cancer Res 1998; 58: 509-511
  PubMedGoogle Scholar
• 95 De Villiers EM, Fauquet C, Broker TR et al. Classification of papillomaviruses. Virology 2004; 324: 17-27
  CrossrefPubMedGoogle Scholar
• 96 Zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002; 2: 342-350
  CrossrefPubMedGoogle Scholar
• 97 Petry KU, Scheffel D, Bode U et al. Cellular immunodeficiency enhances the progression of human papillomavirus-associated cervical lesions. Int J Cancer 1994; 57: 836-840
  CrossrefPubMedGoogle Scholar
• 98 Doorbar J. The papillomavirus life cycle. J Clin Virol 2005; 32 (Suppl. 01) S7-S15
  PubMedGoogle Scholar
• 99 Duensing S, Lee LY, Duensing A et al. The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle. Proc Natl Acad Sci USA 2000; 97: 10002-10007
  CrossrefPubMedGoogle Scholar
• 100 Duensing S, Munger K. Human papillomavirus type 16 E7 oncoprotein can induce abnormal centrosome duplication through a mechanism independent of inactivation of retinoblastoma protein family members. J Virol 2003; 77: 12331-12335
  CrossrefPubMedGoogle Scholar
• 101 Von Knebel Doeberitz M, Bauknecht T, Bartsch D et al. Influence of chromosomal integration on glucocorticoid-regulated transcription of growth-stimulating papillomavirus genes E6 and E7 in cervical carcinoma cells. Proc Natl Acad Sci USA 1991; 88: 1411-1415
  CrossrefPubMedGoogle Scholar
• 102 Von Knebel Doeberitz M, Oltersdorf T, Schwarz E et al. Correlation of modified human papilloma virus early gene expression with altered growth properties in C4-1 cervical carcinoma cells. Cancer Res 1988; 48: 3780-3786
  PubMedGoogle Scholar
• 103 Kessis TD, Connolly DC, Hedrick L et al. Expression of HPV16 E6 or E7 increases integration of foreign DNA. Oncogene 1996; 13: 427-431
  PubMedGoogle Scholar
• 104 Romanczuk H, Howley PM. Disruption of either the E1 or the E2 regulatory gene of human papillomavirus type 16 increases viral immortalization capacity. Proc Natl Acad Sci USA 1992; 89: 3159-3163
  CrossrefPubMedGoogle Scholar
• 105 Jeon S, Lambert PF et al. Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis. Proc Natl Acad Sci USA 1995; 92: 1654-1658
  CrossrefPubMedGoogle Scholar
• 106 Luft F, Klaes R, Nees M et al. Detection of integrated papillomavirus sequences by ligation-mediated PCR (DIPS-PCR) and molecular characterization in cervical cancer cells. Int J Cancer 2001; 92: 9-17
  CrossrefPubMedGoogle Scholar
• 107 Wentzensen N, Ridder R, Klaes R et al. Characterization of viral-cellular fusion transcripts in a large series of HPV16 and 18 positive anogenital lesions. Oncogene 2002; 21: 419-426
  CrossrefPubMedGoogle Scholar
• 108 Butel JS. Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis 2000; 21: 405-426
  CrossrefPubMedGoogle Scholar
• 109 Dall KL, Scarpini CG, Roberts I et al. Characterization of naturally occurring HPV16 integration sites isolated from cervical keratinocytes under noncompetitive conditions. Cancer Res 2008; 68: 8249-8259
  CrossrefPubMedGoogle Scholar
• 110 Ferris RL, Martinez I, Sirianni N et al. Human papillomavirus-16 associated squamous cell carcinoma of the head and neck (SCCHN): a natural disease model provides insights into viral carcinogenesis. Eur J Cancer 2005; 41: 807-815
  CrossrefPubMedGoogle Scholar
• 111 Rampias T, Sasaki C, Weinberger P et al. E6 and e7 gene silencing and transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells. J Natl Cancer Inst 2009; 101: 412-423
  CrossrefPubMedGoogle Scholar
• 112 Gasco M, Crook T. The p53 network in head and neck cancer. Oral Oncol 2003; 39: 222-231
  CrossrefPubMedGoogle Scholar
• 113 Hafkamp HC, Speel EJ, Haesevoets A et al. A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5-8. Int J Cancer 2003; 107: 394-400
  CrossrefPubMedGoogle Scholar
• 114 Psyrri A, Prezas L, Burtness B. Oropharyngeal cancer. Clin Adv Hematol Oncol 2008; 6: 604-612
  PubMedGoogle Scholar
• 115 Dai M, Clifford GM, Le Calvez F et al. Human papillomavirus type 16 and TP53 mutation in oral cancer: matched analysis of the IARC multicenter study. Cancer Res 2004; 64: 468-471
  CrossrefPubMedGoogle Scholar
• 116 Weinberger PM, Yu Z, Kountourakis P et al. Defining molecular phenotypes of human papillomavirus-associated oropharyngeal squamous cell carcinoma: validation of three-class hypothesis. Otolaryngol Head Neck Surg 2009; 141: 382-389
  CrossrefPubMedGoogle Scholar
• 117 Stenner M, Yosef B, Huebbers CU et al. Nuclear translocation of beta-catenin and decreased expression of epithelial cadherin in human papillomavirus-positive tonsillar cancer: an early event in human papillomavirus-related tumour progression?. Histopathology 2011; 58: 1117-1126
  CrossrefPubMedGoogle Scholar
• 118 Furusawa J, Zhang H, Vural E et al. Distinct epigenetic profiling in head and neck squamous cell carcinoma stem cells. Otolaryngol Head Neck Surg 2011; 144: 900-909
  CrossrefPubMedGoogle Scholar
• 119 Sartor MA, Dolinoy DC, Jones TR 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: 777-787
  CrossrefPubMedGoogle Scholar
• 120 Park IS, Chang X, Loyo M et al. Characterization of the methylation patterns in human papillomavirus type 16 viral DNA in head and neck cancers. Cancer Prev Res (Phila) 2011; 4: 207-217
  CrossrefPubMedGoogle Scholar
• 121 Cervigne NK, Reis PP, Machado J et al. Identification of a microRNA signature associated with progression of leukoplakia to oral carcinoma. Hum Mol Genet 2009; 18: 4818-4829
  CrossrefPubMedGoogle Scholar
• 122 Liu X, Jiang L, Wang A. MicroRNA-138 suppresses invasion and promotes apoptosis in head and neck squamous cell carcinoma cell lines. Cancer Lett 2009; 286: 217-222
  CrossrefPubMedGoogle Scholar
• 123 Liu X, Yu J, Jiang L et al. MicroRNA-222 regulates cell invasion by targeting matrix metalloproteinase 1 (MMP1) and manganese superoxide dismutase 2 (SOD2) in tongue squamous cell carcinoma cell lines. Cancer Genomics Proteomics 2009; 6: 131-139
  PubMedGoogle Scholar
• 124 Yu ZW, Zhong LP, Ji T et al. MicroRNAs contribute to the chemoresistance of cisplatin in tongue squamous cell carcinoma lines. Oral Oncol 2010; 46: 317-322
  CrossrefPubMedGoogle Scholar
• 125 Lajer CB, Nielsen FC, Friis-Hansen L. Different miRNA signatures of oral and pharyngeal squamous cell carcinomas: a prospective translational study. Br J Cancer 2011; 104: 830-840
  CrossrefPubMedGoogle Scholar
• 126 Wald AI, Hoskins EE, Wells SI et al. Alteration of microRNA profiles in squamous cell carcinoma of the head and neck cell lines by human papillomavirus. Head Neck 2011; 33: 504-512
  CrossrefPubMedGoogle Scholar
• 127 Holleman A, Chung I, Olsen RR et al. miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo. Oncogene 2011;
  PubMedGoogle Scholar
• 128 Nagel R, Le Sage C, Diosdado B et al. Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res 2008; 68: 5795-5802
  CrossrefPubMedGoogle Scholar
• 129 Liu CJ, Kao SY, Tu HF. Increase of microRNA miR-31 level in plasma could be a potential marker of oral cancer. Oral Dis 2010; 16: 360-364
  CrossrefPubMedGoogle Scholar
• 130 Park NJ, Zhou H, Elashoff D et al. Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res 2009; 15: 5473-5477
  CrossrefPubMedGoogle Scholar
• 131 Wollenberg B. Implication of stem cells in the biology and therapy of head and neck cancer. Laryngorhinootologie 2011; 90 (Suppl. 01) S110-S119
  Article in Thieme ConnectPubMedGoogle Scholar
• 132 Garrity T, Pandit R, Wright MA et al. Increased presence of CD34+ cells in the peripheral blood of head and neck cancer patients and their differentiation into dendritic cells. Int J Cancer 1997; 73: 663-669
  CrossrefPubMedGoogle Scholar
• 133 Pandit R, Lathers DM, Beal NM et al. CD34+ immune suppressive cells in the peripheral blood of patients with head and neck cancer. Ann Otol Rhinol Laryngol 2000; 109: 749-754
  PubMedGoogle Scholar
• 134 Young MR, Petruzzelli GJ, Kolesiak K et al. Human squamous cell carcinomas of the head and neck chemoattract immune suppressive CD34(+) progenitor cells. Hum Immunol 2001; 62: 332-341
  CrossrefPubMedGoogle Scholar
• 135 Tabor MH, Clay MR, Owen JH et al. Head and neck cancer stem cells: the side population. Laryngoscope 2011; 121: 527-533
  CrossrefPubMedGoogle Scholar
• 136 Martens JE, Arends J, Van Der Linden PJ et al. Cytokeratin 17 and p63 are markers of the HPV target cell, the cervical stem cell. Anticancer Res 2004; 24: 771-775
  PubMedGoogle Scholar
• 137 Regenbrecht CR, Lehrach H, Adjaye J. Stemming cancer: functional genomics of cancer stem cells in solid tumors. Stem Cell Rev 2008; 4: 319-328
  CrossrefPubMedGoogle Scholar
• 138 Wittekindt C, Wagner S, Klussmann JP. HPV-associated head and neck cancer : The basics of molecular and translational research. HNO 2011;
  PubMedGoogle Scholar
• 139 Cuzick J, Szarewski A, Cubie H et al. Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet 2003; 362: 1871-1876
  CrossrefPubMedGoogle Scholar
• 140 Schiffman M, Castle PE, Jeronimo J et al. Human papillomavirus and cervical cancer. Lancet 2007; 370: 890-907
  CrossrefPubMedGoogle Scholar
• 141 Raffle AE, Alden B, Quinn M et al. Outcomes of screening to prevent cancer: analysis of cumulative incidence of cervical abnormality and modelling of cases and deaths prevented. BMJ 2003; 326: 901
  CrossrefPubMedGoogle Scholar
• 142 Wallin KL, Wiklund F, Angstrom T et al. Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. N Engl J Med 1999; 341: 1633-1638
  CrossrefPubMedGoogle Scholar
• 143 Wentzensen N, Vinokurova S, Von Knebel Doeberitz M. 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: 3878-3884
  CrossrefPubMedGoogle Scholar
• 144 Andrews E, Shores C, Hayes DN et al. Concurrent human papillomavirus-associated tonsillar carcinoma in 2 couples. J Infect Dis 2009; 200: 882-887
  CrossrefPubMedGoogle Scholar
• 145 Giraldo P, Goncalves AK, Pereira SA et al. Human papillomavirus in the oral mucosa of women with genital human papillomavirus lesions. Eur J Obstet Gynecol Reprod Biol 2006; 126: 104-106
  CrossrefPubMedGoogle Scholar
• 146 Hemminki K, Dong C. Cancer in husbands of cervical cancer patients. Epidemiology 2000; 11: 347-349
  CrossrefPubMedGoogle Scholar
• 147 Roberts JN, Buck CB, Thompson CD et al. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nat Med 2007; 13: 857-861
  CrossrefPubMedGoogle Scholar
• 148 Begum S, Cao D, Gillison M et al. Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clin Cancer Res 2005; 11: 5694-5699
  CrossrefPubMedGoogle Scholar
• 149 Kim JS, Crooks H, Foxworth A et al. Proof-of-principle: oncogenic beta-catenin is a valid molecular target for the development of pharmacological inhibitors. Mol Cancer Ther 2002; 1: 1355-1359
  PubMedGoogle Scholar
• 150 Sant M, Aareleid T, Berrino F et al. EUROCARE-3: survival of cancer patients diagnosed 1990–94 – results and commentary. Ann Oncol 2003; 14 (Suppl. 05) v61-v118
  CrossrefPubMedGoogle Scholar
• 151 Guntinas-Lichius O, Wendt T, Buentzel J et al. Head and neck cancer in Germany: a site-specific analysis of survival of the Thuringian cancer registration database. J Cancer Res Clin Oncol 2010; 136: 55-63
  CrossrefPubMedGoogle Scholar
• 152 Weber A, Schmid KW, Tannapfel A et al. Changes in the TNM classification of head and neck tumors. Pathologe 2010; 31: 339-343
  CrossrefPubMedGoogle Scholar
• 153 Preuss SF, Klussmann JP, Wittekindt C et al. Long-term results of the combined modality therapy for advanced cervical metastatic head and neck squamous cell carcinoma. Eur J Surg Oncol 2007; 33: 358-363
  CrossrefPubMedGoogle Scholar
• 154 Preuss SF, Cramer K, Klussmann JP et al. Transoral laser surgery for laryngeal cancer: outcome, complications and prognostic factors in 275 patients. Eur J Surg Oncol 2009; 35: 235-240
  CrossrefPubMedGoogle Scholar
• 155 Psychogios G, Waldfahrer F, Bozzato A et al. Evaluation of the revised TNM classification in advanced laryngeal cancer. Eur Arch Otorhinolaryngol 2010; 267: 117-121
  CrossrefPubMedGoogle Scholar
• 156 Hall SF, Groome PA, Irish J et al. TNM-based stage groupings in head and neck cancer: application in cancer of the hypopharynx. Head Neck 2009; 31: 1-8
  CrossrefPubMedGoogle Scholar
• 157 Kreppel M, Eich HT, Kubler A et al. Prognostic value of the sixth edition of the UICC’s TNM classification and stage grouping for oral cancer. J Surg Oncol 2010; 102: 443-449
  CrossrefPubMedGoogle Scholar
• 158 Groome PA, Schulze KM, Mackillop WJ et al. A comparison of published head and neck stage groupings in carcinomas of the tonsillar region. Cancer 2001; 92: 1484-1494
  CrossrefPubMedGoogle Scholar
• 159 Byers RM, Bland KI, Borlase B et al. The prognostic and therapeutic value of frozen section determinations in the surgical treatment of squamous carcinoma of the head and neck. Am J Surg 1978; 136: 525-528
  CrossrefPubMedGoogle Scholar
• 160 Guillemaud JP, Patel RS, Goldstein DP et al. Prognostic impact of intraoperative microscopic cut-through on frozen section in oral cavity squamous cell carcinoma. J Otolaryngol Head Neck Surg 2010; 39: 370-377
  PubMedGoogle Scholar
• 161 Ganly I, Patel S, Shah J. Early stage squamous cell cancer of the oral tongue-clinicopathologic features affecting outcome. Cancer 2011;
  PubMedGoogle Scholar
• 162 Mohit-Tabatabai MA, Sobel HJ, Rush BF et al. Relation of thickness of floor of mouth stage I and II cancers to regional metastasis. Am J Surg 1986; 152: 351-353
  CrossrefPubMedGoogle Scholar
• 163 Jeremic B, Milicic B. Pretreatment prognostic factors of survival in patients with locally advanced nonmetastatic squamous cell carcinoma of the head and neck treated with radiation therapy with or without concurrent chemotherapy. Am J Clin Oncol 2009; 32: 163-168
  CrossrefPubMedGoogle Scholar
• 164 Ang KK, Harris J, Wheeler R et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363: 24-35
  CrossrefPubMedGoogle Scholar
• 165 De Graeff A, De Leeuw JR, Ros WJ et al. Sociodemographic factors and quality of life as prognostic indicators in head and neck cancer. Eur J Cancer 2001; 37: 332-339
  CrossrefPubMedGoogle Scholar
• 166 Poeta ML, Manola J, Goldwasser MA et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med 2007; 357: 2552-2561
  CrossrefPubMedGoogle Scholar
• 167 Brennan JA, Mao L, Hruban RH et al. Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. N Engl J Med 1995; 332: 429-435
  CrossrefPubMedGoogle Scholar
• 168 Sardi I, Franchi A, Ferriero G et al. Prediction of recurrence by microsatellite analysis in head and neck cancer. Genes Chromosomes Cancer 2000; 29: 201-206
  CrossrefPubMedGoogle Scholar
• 169 Martone T, Gillio-Tos A, De Marco L et al. Association between hypermethylated tumor and paired surgical margins in head and neck squamous cell carcinomas. Clin Cancer Res 2007; 13: 5089-5094
  CrossrefPubMedGoogle Scholar
• 170 Nathan CO, Liu L, Li BD et al. Detection of the proto-oncogene eIF4E in surgical margins may predict recurrence in head and neck cancer. Oncogene 1997; 15: 579-584
  CrossrefPubMedGoogle Scholar
• 171 Harden SV, Thomas DC, Benoit N et al. Real-time gap ligase chain reaction: a rapid semiquantitative assay for detecting p53 mutation at low levels in surgical margins and lymph nodes from resected lung and head and neck tumors. Clin Cancer Res 2004; 10: 2379-2385
  CrossrefPubMedGoogle Scholar
• 172 Fakhry C, Westra WH, Li S 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: 261-269
  CrossrefPubMedGoogle Scholar
• 173 Pang E, Delic NC, Hong A et al. Radiosensitization of oropharyngeal squamous cell carcinoma cells by human papillomavirus 16 oncoprotein E6 *I. Int J Radiat Oncol Biol Phys 2011; 79: 860-865
  CrossrefPubMedGoogle Scholar
• 174 Fischer CA, Kampmann M, Zlobec I et al. p16 expression in oropharyngeal cancer: its impact on staging and prognosis compared with the conventional clinical staging parameters. Ann Oncol 2010; 21: 1961-1966
  CrossrefPubMedGoogle Scholar
• 175 Straetmans JM, Olthof N, Mooren JJ et al. Human papillomavirus reduces the prognostic value of nodal involvement in tonsillar squamous cell carcinomas. Laryngoscope 2009; 119: 1951-1957
  CrossrefPubMedGoogle Scholar
• 176 Fischer CA, Zlobec I, Green E et al. Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality?. Int J Cancer 2010; 126: 1256-1262
  PubMedGoogle Scholar
• 177 Licitra L, Perrone F, Bossi P et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 2006; 24: 5630-5636
  CrossrefPubMedGoogle Scholar
• 178 Hafkamp HC, Mooren JJ, Claessen SM et al. P21 Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis. Mod Pathol 2009; 22: 686-698
  CrossrefPubMedGoogle Scholar
• 179 Preuss SF, Weinell A, Molitor M et al. Nuclear survivin expression is associated with HPV-independent carcinogenesis and is an indicator of poor prognosis in oropharyngeal cancer. Br J Cancer 2008; 98: 627-632
  CrossrefPubMedGoogle Scholar
• 180 Ang KK, Berkey BA, Tu X et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002; 62: 7350-7356
  PubMedGoogle Scholar
• 181 Kumar B, Cordell KG, Lee JS et al. EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 2008; 26: 3128-3137
  CrossrefPubMedGoogle Scholar
• 182 Reimers N, Kasper HU, Weissenborn SJ et al. Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer 2007; 120: 1731-1738
  CrossrefPubMedGoogle Scholar
• 183 Sok JC, Coppelli FM, Thomas SM 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: 5064-5073
  CrossrefPubMedGoogle Scholar
• 184 Hama T, Yuza Y, Saito Y et al. Prognostic significance of epidermal growth factor receptor phosphorylation and mutation in head and neck squamous cell carcinoma. Oncologist 2009; 14: 900-908
  CrossrefPubMedGoogle Scholar
• 185 Nakata Y, Uzawa N, Takahashi KI et al. EGFR gene copy number alteration is a better prognostic indicator than protein overexpression in oral tongue squamous cell carcinomas. Eur J Cancer 2011;
  PubMedGoogle Scholar
• 186 Sheu JJ, Hua CH, Wan L et al. Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma. Cancer Res 2009; 69: 2568-2576
  CrossrefPubMedGoogle Scholar
• 187 Knudsen BS, Vande Woude G. Showering c-MET-dependent cancers with drugs. Curr Opin Genet Dev 2008; 18: 87-96
  CrossrefPubMedGoogle Scholar
• 188 Smeets SJ, Hesselink AT, Speel EJ et al. A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer 2007; 121: 2465-2472
  CrossrefPubMedGoogle Scholar
• 189 Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567-578
  CrossrefPubMedGoogle Scholar
• 190 Vermorken JB, Mesia R, Rivera F et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116-1127
  CrossrefPubMedGoogle Scholar
• 191 Huang S, Armstrong EA, Benavente S et al. Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res 2004; 64: 5355-5362
  CrossrefPubMedGoogle Scholar
• 192 Stewart JS, Cohen EE, Licitra L et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009; 27: 1864-1871
  CrossrefPubMedGoogle Scholar
• 193 Abidoye OO, Cohen EE, Wong SJ et al. A phase II study of lapatinib (GW572016) in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 2006; 24: 297S
  PubMedGoogle Scholar
• 194 Punt CJ, Nagy A, Douillard JY et al. Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet 2002; 360: 671-677
  CrossrefPubMedGoogle Scholar