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Age-specific oncogenic pathways in head and neck squamous cell carcinoma - are elderly a different subcategory?

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Abstract

Background

In recent clinical practice, an increasing number of elderly patients suffering from head and neck squamous cell carcinoma (HNSCC) of unknown pathophysiology is observed. The majority of HNSCC patients can roughly be divided into three subcategories. First, a small group of young patients who present with variants of genomic aberrations and inheritable diseases like Fanconi anaemia. Second, an increasing population of HPV-related HNSCCs that are regarded as genomic stable tumours with a more favourable prognosis. Though HPV-related tumours used to be more common among younger males, a notable rise in the elderly population is observed. The third subcategory, that of HPV-negative tumours, has been shown to be more heterogeneous with involvement of a variety of oncogenic pathways related to lifestyle factors like smoking and alcohol consumption, often seen in middle-aged males. Some of these pathways could be related to age, such as TP53 alterations, EGFR activation, apoptotic pathway alterations and field cancerization.

Conclusions

In this narrative review, we provide an overview of established and newly discovered age-specific pathophysiological mechanisms underlying HNSCC. We propose a fourth subcategory of patients with a suspected different pathophysiology: elderly (HPV-negative) HNSCC patients without a history of tobacco and alcohol consumption. In this subcategory, carcinogenesis seems to be a multi-step process based on genomic instability, immunosenescence, cell cycle disruption and telomere shortening. To conclude, we discuss suggestions for future research to fill the knowledge gap about age-dependent HNSCC carcinogenesis.

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Not Applicable as the manuscript is a review containing no original data.

References

  1. F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J. Clin. 68, 394–424 (2018). https://doi.org/10.3322/caac.21492.

  2. J. Ferlay, M. Colombet, I. Soerjomataram, C. Mathers, D.M. Parkin, M. Piñeros, A. Znaor, F. Bray, Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer 144, 1941–1953 (2019). https://doi.org/10.1002/ijc.31937

    Article  CAS  PubMed  Google Scholar 

  3. H.S. Van Monsjou, V.B. Wreesmann, M.W.M. Van Den Brekel, A.J.M. Balm, Head and neck squamous cell carcinoma in young patients. Oral Oncol. 49, 1097–1102 (2013). https://doi.org/10.1016/j.oraloncology.2013.09.001

    Article  PubMed  Google Scholar 

  4. R. Venugopal, R. M. Bavle, P. Konda, S. Muniswamappa, S. Makarla, Familial cancers of head and neck region. J. Clin. Diagn. Res. 11, ZE01–ZE06 (2017). https://doi.org/10.7860/JCDR/2017/25920.9967.

  5. A.K. Chaturvedi, E.A. Engels, W.F. Anderson, M.L. Gillison, Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J. Clin. Oncol. 26, 612–619 (2008). https://doi.org/10.1200/JCO.2007.14.1713

    Article  PubMed  Google Scholar 

  6. F. Dayyani, C.J. Etzel, M. Liu, C.H. Ho, S.M. Lippman, A.S. Tsao, Meta-analysis of the impact of human papillomavirus (HPV) on cancer risk and overall survival in head and neck squamous cell carcinomas (HNSCC). Head Neck Oncol. 2, 15 (2010). https://doi.org/10.1186/1758-3284-2-15

    Article  PubMed  PubMed Central  Google Scholar 

  7. K.K. Ang, J. Harris, R. Wheeler, R. Weber, D.I. Rosenthal, P.F. Nguyen-Tân, W.H. Westra, C.H. Chung, R.C. Jordan, C. Lu, H. Kim, R. Axelrod, C.C. Silverman, K.P. Redmond, M.L. Gillison, Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 363, 24–35 (2010). https://doi.org/10.1056/nejmoa0912217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. B. O’Sullivan, S.H. Huang, J. Su, A.S. Garden, E.M. Sturgis, K. Dahlstrom, N. Lee, N. Riaz, X. Pei, S.A. Koyfman, D. Adelstein, B.B. Burkey, J. Friborg, C.A. Kristensen, A.B. Gothelf, F. Hoebers, B. Kremer, E.J. Speel, D.W. Bowles, D. Raben, S.D. Karam, E. Yu, W. Xu, Development and validation of a staging system for HPV-related oropharyngeal cancer by the international collaboration on oropharyngeal cancer network for staging (ICON-S): a multicentre cohort study. Lancet Oncol. 17, 440–451 (2016). https://doi.org/10.1016/S1470-2045(15)00560-4

    Article  PubMed  Google Scholar 

  9. A. Villepelet, S. Hugonin, S. Atallah, B. Job, B. Baujat, J. Lacau St Guily, R. Lacave, Effects of tobacco abuse on major chromosomal instability in human papilloma virus 16-positive oropharyngeal squamous cell carcinoma. Int. J. Oncol. 55, 527–535 (2019). https://doi.org/10.3892/ijo.2019.4826.

  10. N. Howlader, A. M. Noone, M. Krapcho, J. Garshell, D. Miller, S. F. Altekruse, C. L. Kosary, M. Yu, J. Ruhl, Z. Tatalovich, A. Mariotto, D. R. Lewis, H. S. Chen, E. J. Feuer, K. A. Cronin, SEER Cancer Statistics Review, 1975–2011, National Cancer Institute. Based on November 2013 SEER data submission, posted to the SEER web site, April 2014. Seercancergov/Csr. (2014). Accessed October 2020.

  11. C.R. Leemans, P.J.F. Snijders, R.H. Brakenhoff, The molecular landscape of head and neck cancer. Nat. Rev. Cancer 18, 269–282 (2018). https://doi.org/10.1038/nrc.2018.11

    Article  CAS  PubMed  Google Scholar 

  12. S. Hartmann, J.R. Grandis, Treatment of head and neck cancer in the elderly. Expert Opin. Pharmacother. 17, 1903–1921 (2016). https://doi.org/10.1080/14656566.2016.1220540

    Article  CAS  PubMed  Google Scholar 

  13. T.T.A. Peters, B.A.C. Van Dijk, J.L.N. Roodenburg, B.F.A.M. Van Der Laan, G.B. Halmos, Relation between age, comorbidity, and complications in patients undergoing major surgery for head and neck cancer. Ann. Surg. Oncol. 21, 963–970 (2014). https://doi.org/10.1245/s10434-013-3375-x

    Article  PubMed  Google Scholar 

  14. J.R. Aunan, W.C. Cho, K. Søreide, The biology of aging and cancer: a brief overview of shared and divergent molecular hallmarks. Aging Dis. 8, 628–642 (2017). https://doi.org/10.14336/AD.2017.0103

    Article  PubMed  PubMed Central  Google Scholar 

  15. C.R. Leemans, B.J.M. Braakhuis, R.H. Brakenhoff, The molecular biology of head and neck cancer. Nat. Rev. Cancer 11, 9–22 (2011). https://doi.org/10.1038/nrc2982

    Article  CAS  PubMed  Google Scholar 

  16. S.S. Prime, N.S. Thakker, M. Pring, P.G. Guest, I.C. Paterson, A review of inherited cancer syndromes and their relevance to oral squamous cell carcinoma. Oral Oncol. 37, 1–16 (2001). https://doi.org/10.1016/S1368-8375(00)00055-5

    Article  CAS  PubMed  Google Scholar 

  17. A.T. Wang, A. Smogorzewska, SnapShot: fanconi anemia and associated proteins. Cell 160, 354-354.e1 (2015). https://doi.org/10.1016/j.cell.2014.12.031

    Article  CAS  PubMed  Google Scholar 

  18. C. Turke, S. Horn, C. Petto, D. Labudde, G. Lauer, G. Wittenburg, Loss of heterozygosity in FANCG, FANCF and BRIP1 from head and neck squamous cell carcinoma of the oral cavity. Int. J. Oncol. 50, 2207–2220 (2017). https://doi.org/10.3892/ijo.2017.3974

    Article  CAS  PubMed  Google Scholar 

  19. V.B. Wreesmann, C. Estilo, D.W. Eisele, B. Singh, S.J. Wang, Downregulation of fanconi anemia genes in sporadic head and neck squamous cell carcinoma. ORL J. Otorhinolaryngol. Relat. Spec.  69, 218–225 (2007). https://doi.org/10.1159/000101542

    Article  CAS  PubMed  Google Scholar 

  20. S.C. Chandrasekharappa, S.B. Chinn, F.X. Donovan, N.I. Chowdhury, A. Kamat, A.A. Adeyemo, J.W. Thomas, M. Vemulapalli, C.S. Hussey, H.H. Reid, J.C. Mullikin, Q. Wei, E.M. Sturgis, Assessing the spectrum of germline variation in fanconi anemia genes among patients with head and neck carcinoma before age 50. Cancer 123, 3943–3954 (2017). https://doi.org/10.1002/cncr.30802

    Article  CAS  PubMed  Google Scholar 

  21. S. Tremblay, P.P. Dos Reis, G. Bradley, N.N. Galloni, B. Perez-Ordonez, J. Freeman, D. Brown, R. Gilbert, P. Gullane, J. Irish, S. Kamel-Reid, Young patients with oral squamous cell carcinoma: study of the involvement of GSTP1 and deregulation of the fanconi anemia genes. Arch. Otolaryngol. Head Neck Surg. 132, 958–966 (2006). https://doi.org/10.1001/archotol.132.9.958

    Article  PubMed  Google Scholar 

  22. J.X. Bei, W.H. Jia, Y.X. Zeng, Familial and large-scale case-control studies identify genes associated with nasopharyngeal carcinoma. Semin. Cancer Biol. 22, 96–106 (2012). https://doi.org/10.1016/j.semcancer.2012.01.012

    Article  CAS  PubMed  Google Scholar 

  23. M. S. Fernández García, J. Teruya-Feldstein, The diagnosis and treatment of dyskeratosis congenita: A review. J. Blood Med. 5, 157–167 (2014). https://doi.org/10.2147/JBM.S47437.

  24. C. Cunniff, J.A. Bassetti, N.A. Ellis, Bloom’s syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition. Mol. Syndromol. 8, 4–23 (2017). https://doi.org/10.1159/000452082

    Article  CAS  PubMed  Google Scholar 

  25. A.S. Berkower, H.F. Biller, Head and neck cancer associated with bloom’s syndrome. Laryngoscope 98, 746–748 (1988). https://doi.org/10.1288/00005537-198807000-00012

    Article  CAS  PubMed  Google Scholar 

  26. A.M.R. Taylor, C. Rothblum-Oviatt, N.A. Ellis, I.D. Hickson, S. Meyer, T.O. Crawford, A. Smogorzewska, B. Pietrucha, C. Weemaes, G.S. Stewart, Chromosome instability syndromes. Nat. Rev. Dis. Primers. 5, 64 (2019). https://doi.org/10.1038/s41572-019-0113-0

    Article  PubMed  Google Scholar 

  27. P.L. Friedlander, Genomic instability in head and neck cancer patients. Head Neck 23, 683–691 (2001). https://doi.org/10.1002/hed.1096

    Article  CAS  PubMed  Google Scholar 

  28. O. Michaeli, D. Malkin, Li-Fraumeni Syndrome. Encyclopedia of cancer. 356–368 (2018). https://doi.org/10.1016/B978-0-12-801238-3.96122-1.

  29. M. Akashi, H.P. Koeffler, Li-Fraumeni syndrome and the role of the p53 tumor suppressor gene in cancer susceptibility. Clin. Obstet. Gynecol. 41, 172–199 (1998). https://doi.org/10.1097/00003081-199803000-00024

    Article  CAS  PubMed  Google Scholar 

  30. T.N. Toporcov, A. Znaor, Z.F. Zhang, G.P. Yu, D.M. Winn, Q. Wei, M. Vilensky, T. Vaughan, P. Thomson, R. Talamini, N. Szeszenia-Dabrowska, E.M. Sturgis, E. Smith, O. Shangina, S.M. Schwartz, S. Schantz, P. Rudnai, L. Richiardi, H. Ramroth, M.P. Purdue, A.F. Olshan, J. Eluf-Neto, J. Muscat, R.A. Moyses, H. Morgenstern, A. Menezes, M. McClean, K. Matsuo, D. Mates, T.V. Macfarlane, J. Lissowska, F. Levi, P. Lazarus, C. La Vecchia, P. Lagiou, S. Koifman, K. Kjaerheim, K. Kelsey, I. Holcatova, R. Herrero, C. Healy, R.B. Hayes, S. Franceschi, L. Fernandez, E. Fabianova, A.W. Daudt, O.A. Curioni, L.D. Maso, M.P. Curado, D.I. Conway, C. Chen, X. Castellsague, C. Canova, G. Cadoni, P. Brennan, S. Boccia, J.L.F. Antunes, W. Ahrens, A. Agudo, P. Boffetta, M. Hashibe, Y.C.A. Lee, V.W. Filho, Risk Factors for Head and Neck Cancer in Young Adults: A Pooled Analysis in the INHANCE Consortium. Int. J. Epidemiol. 44, 169–185 (2015). https://doi.org/10.1093/ije/dyu255

    Article  PubMed  PubMed Central  Google Scholar 

  31. A.R. Kreimer, G.M. Clifford, P. Boyle, S. Franceschi, Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systemic review. Cancer Epidemiol. Biomark. Prev. 14, 467–475 (2005). https://doi.org/10.1158/1055-9965.EPI-04-0551

    Article  CAS  Google Scholar 

  32. C. Ndiaye, M. Mena, L. Alemany, M. Arbyn, X. Castellsagué, L. Laporte, F.X. Bosch, S. de Sanjosé, H. Trottier, HPV DNA, E6/E7 MRNA, and P16INK4a detection in head and neck cancers: a systematic review and meta-analysis. Lancet Oncol. 15, 1319–1331 (2014). https://doi.org/10.1016/S1470-2045(14)70471-1

    Article  CAS  PubMed  Google Scholar 

  33. P. S. Hammerman, D. Neil Hayes, J. R. Grandis, Therapeutic insights from genomic studies of head and neck squamous cell carcinomas. Cancer Discov. 5, 239–244 (2015). https://doi.org/10.1158/2159-8290.CD-14-1205.

  34. D. Rischin, R. J. Young, R. Fisher, S. B. Fox, Q. T. Le, L. J. Peters, B. Solomon, J. Choi, B. O’Sullivan, L. M. Kenny, G. A. McArthur, Prognostic significance of P16INK4Aand human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 Phase III Trial. J. Clin. Oncol. 28, 4142–4148 (2010). https://doi.org/10.1200/JCO.2010.29.2904.

  35. M.L. Gillison, Current topics in the epidemiology of oral cavity and oropharyngeal cancers. Head Neck 29, 779–792 (2007). https://doi.org/10.1002/hed.20573

    Article  PubMed  Google Scholar 

  36. G. D’Souza, A.R. Kreimer, R. Viscidi, M. Pawlita, C. Fakhry, W.M. Koch, W.H. Westra, M.L. Gillison, Case-control study of human papillomavirus and oropharyngeal cancer. N. Engl. J. Med. 356, 1944–1956 (2007). https://doi.org/10.1056/nejmoa065497

    Article  PubMed  Google Scholar 

  37. H.J. Ryu, E.K. Kim, B.C. Cho, S.O. Yoon, Characterization of head and neck squamous cell carcinoma arising in young patients: particular focus on molecular alteration and tumor immunity. Head Neck 41, 198–207 (2019). https://doi.org/10.1002/hed.25507

    Article  PubMed  Google Scholar 

  38. Z.S. Zumsteg, G. Cook-Wiens, E. Yoshida, S.L. Shiao, N.Y. Lee, A. Mita, C. Jeon, M.T. Goodman, A.S. Ho, Incidence of oropharyngeal cancer among elderly patients in the United States. JAMA Oncol. 2, 1617–1623 (2016). https://doi.org/10.1001/jamaoncol.2016.1804

    Article  PubMed  Google Scholar 

  39. B. Solomon, R.J. Young, D. Rischin, Head and neck squamous cell carcinoma: genomics and emerging biomarkers for immunomodulatory cancer treatments. Semin. Cancer Biol. 52, 228–240 (2018). https://doi.org/10.1016/j.semcancer.2018.01.008

    Article  CAS  PubMed  Google Scholar 

  40. S. Stone, P. Jiang, P. Dayananth, S.V. Tavtigian, H. Katcher, D. Parry, G. Peters, A. Kamb, Complex structure and regulation of the P16 (MTS1) locus. Cancer Res. 55, 2988–2994 (1995)

    CAS  Google Scholar 

  41. G.I. Shapiro, C.D. Edwards, L. Kobzik, J. Godleski, W. Richards, D.J. Sugarbaker, B.J. Rollins, Reciprocal Rb inactivation and P16INK4 expression in primary lung cancers and cell lines. Cancer Res. 55, 505–509 (1995)

    CAS  Google Scholar 

  42. A. Merlo, J.G. Herman, L. Mao, D.J. Lee, E. Gabrielson, P.C. Burger, S.B. Baylin, D. Sidransky, 5’ CpG island méthylation is associated with transcriptional silencing of the tumour suppressor P16/CDKN2/MTS1 in human cancers. Nat. Med. 1, 686–692 (1995). https://doi.org/10.1038/nm0795-686

    Article  CAS  PubMed  Google Scholar 

  43. M. S. Lawrence, C. Sougnez, L. Lichtenstein, K. Cibulskis, E. Lander, S. B. Gabriel, G. Getz, A. Ally, M. Balasundaram, I. Birol, R. Bowlby, D. Brooks, Y. S. N. Butterfield, R. Carlsen, D. Cheng, A. Chu, N. Dhalla, R. Guin, R. A. Holt, S. J. M. Jones, D. Lee, H. I. Li, M. A. Marra, M. Mayo, R. A. Moore, A. J. Mungall, A. G. Robertson, J. E. Schein, P. Sipahimalani, A. Tam, N. Thiessen, T. Wong, A. Protopopov, N. Santoso, S. Lee, M. Parfenov, J. Zhang, H. S. Mahadeshwar, J. Tang, X. Ren, S. Seth, P. Haseley, D. Zeng, L. Yang, A. W. Xu, X. Song, A. Pantazi, C. A. Bristow, A. Hadjipanayis, J. Seidman, L. Chin, P. J. Park, R. Kucherlapati, R. Akbani, T. Casasent, W. Liu, Y. Lu, G. Mills, T. Motter, J. Weinstein, L. Diao, J. Wang, Y. Hong Fan, J. Liu, K. Wang, J. T. Auman, S. Balu, T. Bodenheimer, E. Buda, D. N. Hayes, K. A. Hoadley, A. P. Hoyle, S. R. Jefferys, C. D. Jones, P. K. Kimes, Y. Liu, J. S. Marron, S. Meng, P. A. Mieczkowski, L. E. Mose, J. S. Parker, C. M. Perou, J. F. Prins, J. Roach, Y. Shi, J. V. Simons, D. Singh, M. G. Soloway, D. Tan, U. Veluvolu, V. Walter, S. Waring, M. D. Wilkerson, J. Wu, N. Zhao, A. D. Cherniack, P. S. Hammerman, A. D. Tward, C. S. Pedamallu, G. Saksena, J. Jung, A. I. Ojesina, S. L. Carter, T. I. Zack, S. E. Schumacher, R. Beroukhim, S. S. Freeman, M. Meyerson, J. Cho, M. S. Noble, D. DiCara, H. Zhang, D. I. Heiman, N. Gehlenborg, D. Voet, P. Lin, S. Frazer, P. Stojanov, Y. Liu, L. Zou, J. Kim, D. Muzny, H. V. Doddapaneni, C. Kovar, J. Reid, D. Morton, Y. Han, W. Hale, H. Chao, K. Chang, J. A. Drummond, R. A. Gibbs, N. Kakkar, D. Wheeler, L. Xi, G. Ciriello, M. Ladanyi, W. Lee, R. Ramirez, C. Sander, R. Shen, R. Sinha, N. Weinhold, B. S. Taylor, B. A. Aksoy, G. Dresdner, J. Gao, B. Gross, A. Jacobsen, B. Reva, N. Schultz, S. O. Sumer, Y. Sun, T. A. Chan, L. G. Morris, J. Stuart, S. Benz, S. Ng, C. Benz, C. Yau, S. B. Baylin, L. Cope, L. Danilova, J. G. Herman, M. Bootwalla, D. T. Maglinte, P. W. Laird, T. Triche, D. J. Weisenberger, D. J. Van Den Berg, N. Agrawal, J. Bishop, P. C. Boutros, J. P. Bruce, L. A. Byers, J. Califano, T. E. Carey, Z. Chen, H. Cheng, S. I. Chiosea, E. Cohen, B. Diergaarde, A. M. Egloff, A. K. El-Naggar, R. L. Ferris, M. J. Frederick, J. R. Grandis, Y. Guo, R. I. Haddad, T. Harris, A. B. Y. Hui, J. J. Lee, S. M. Lippman, F. F. Liu, J. B. McHugh, J. Myers, P. K. S. Ng, B. Perez-Ordonez, C. R. Pickering, M. Prystowsky, M. Romkes, A. D. Saleh, M. A. Sartor, R. Seethala, T. Y. Seiwert, H. Si, C. Van Waes, D. M. Waggott, M. Wiznerowicz, W. G. Yarbrough, J. Zhang, Z. Zuo, K. Burnett, D. Crain, J. Gardner, K. Lau, D. Mallery, S. Morris, J. Paulauskis, R. Penny, C. Shelton, T. Shelton, M. Sherman, P. Yena, A. D. Black, J. Bowen, J. Frick, J. M. Gastier-Foster, H. A. Harper, K. Leraas, T. M. Lichtenberg, N. C. Ramirez, L. Wise, E. Zmuda, J. Baboud, M. A. Jensen, A. B. Kahn, T. D. Pihl, D. A. Pot, D. Srinivasan, J. S. Walton, Y. Wan, R. A. Burton, T. Davidsen, J. A. Demchok, G. Eley, M. L. Ferguson, K. R. Mills Shaw, B. A. Ozenberger, M. Sheth, H. J. Sofia, R. Tarnuzzer, Z. Wang, L. Yang, J. C. Zenklusen, C. Saller, K. Tarvin, C. Chen, R. Bollag, P. Weinberger, W. Golusiński, P. Golusiński, M. Ibbs, K. Korski, A. Mackiewicz, W. Suchorska, B. Szybiak, E. Curley, C. Beard, C. Mitchell, G. Sandusky, J. Ahn, Z. Khan, J. Irish, J. Waldron, W. N. William, S. Egea, C. Gomez-Fernandez, L. Herbert, C. R. Bradford, D. B. Chepeha, A. S. Haddad, T. R. Jones, C. M. Komarck, M. Malakh, J. S. Moyer, A. Nguyen, L. A. Peterson, M. E. Prince, L. S. Rozek, E. G. Taylor, H. M. Walline, G. T. Wolf, L. Boice, B. S. Chera, W. K. Funkhouser, M. L. Gulley, T. G. Hackman, M. C. Hayward, M. Huang, W. K. Rathmell, A. H. Salazar, W. W. Shockley, C. G. Shores, L. Thorne, M. C. Weissler, S. Wrenn, A. M. Zanation, B. T. Brown, M. Pham, Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 517, 576–582 (2015). https://doi.org/10.1038/nature14129.

  44. D.N. Hayes, C. Van Waes, T.Y. Seiwert, Genetic landscape of human papillomavirus-associated head and neck cancer and comparison to tobacco-related tumors. J. Clin. Oncol. 33, 3227–3234 (2015). https://doi.org/10.1200/JCO.2015.62.1086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. L.C. Farias, C.A.D.C. Fraga, M.V.M. De Oliveira, T.F. Silva, L. Marques-Silva, P.R. Moreira, A.M.B. De-Paula, R.S. Gomez, A.L.S. Guimarães, Effect of age on the association between P16CDKN2A methylation and DNMT3B polymorphism in head and neck carcinoma and patient survival. Int. J. Oncol. 37, 167–176 (2010). https://doi.org/10.3892/ijo-00000664

    Article  CAS  PubMed  Google Scholar 

  46. T.Y. Seiwert, Z. Zuo, M.K. Keck, A. Khattri, C.S. Pedamallu, T. Stricker, C. Brown, T.J. Pugh, P. Stojanov, J. Cho, M.S. Lawrence, G. Getz, J. Brägelmann, R. DeBoer, R.R. Weichselbaum, A. Langerman, L. Portugal, E. Blair, K. Stenson, M.W. Lingen, E.E.W. Cohen, E.E. Vokes, K.P. White, P.S. Hammerman, Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin. Cancer Res. 21, 632–641 (2015). https://doi.org/10.1158/1078-0432.CCR-13-3310

    Article  CAS  PubMed  Google Scholar 

  47. S. Fulda, K.M. Debatin, Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25, 4798–4811 (2006). https://doi.org/10.1038/sj.onc.1209608

    Article  CAS  PubMed  Google Scholar 

  48. Z. Zhou, E.M. Sturgis, Z. Liu, L.E. Wang, Q. Wei, G. Li, Genetic variants of NOXA and MCL1 modify the risk of HPV16-associated squamous cell carcinoma of the head and neck. BMC Cancer 12, 159 (2012). https://doi.org/10.1186/1471-2407-12-159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Z. Zhou, E.M. Sturgis, Z. Liu, L.E. Wang, Q. Wei, G. Li, Genetic variants of a BH3-Only pro-apoptotic gene, puma, and risk of HPV16-associated squamous cell carcinoma of the head and neck. Mol. Carcinog. 51, E54-64 (2012). https://doi.org/10.1002/mc.21838

    Article  PubMed  Google Scholar 

  50. E.M. Rettig, M. Zaidi, F. Faraji, D.W. Eisele, M. El Asmar, N. Fung, G. D’Souza, C. Fakhry, Oropharyngeal cancer is no longer a disease of younger patients and the prognostic advantage of human papillomavirus is attenuated among older patients: analysis of the national cancer database. Oral Oncol. 83, 147–153 (2018). https://doi.org/10.1016/j.oraloncology.2018.06.013

    Article  PubMed  PubMed Central  Google Scholar 

  51. J.T. Guidry, R.S. Scott, The interaction between human papillomavirus and other viruses. Virus Res. 231, 139–147 (2017). https://doi.org/10.1016/j.virusres.2016.11.002

    Article  CAS  PubMed  Google Scholar 

  52. F. Broccolo, G. Ciccarese, A. Rossi, L. Anselmi, F. Drago, A. Toniolo, Human papillomavirus (HPV) and epstein-barr virus (EBV) in keratinizing versus non- keratinizing squamous cell carcinoma of the oropharynx. Infect. Agents Cancer 13, 32 (2018). https://doi.org/10.1186/s13027-018-0205-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. B. Drop, M. Strycharz-Dudziak, E. Kliszczewska, M. Polz-Dacewicz, Coinfection with Epstein–Barr Virus (EBV), Human Papilloma Virus (HPV) and Polyoma Bk Virus (BKPyV) in laryngeal, oropharyngeal and oral cavity cancer. Int. J. Mol. Sci. 18, (2017). https://doi.org/10.3390/ijms18122752.

  54. D. H. E. Maasland, P. A. van den Brandt, B. Kremer, R. A. (. Goldbohm, L. J. Schouten, Alcohol consumption, cigarette smoking and the risk of subtypes of head-neck cancer: results from the Netherlands cohort study. BMC Cancer 14, 187 (2014). https://doi.org/10.1186/1471-2407-14-187.

  55. N. Riaz, L.G. Morris, W. Lee, T.A. Chan, Unraveling the molecular genetics of head and neck cancer through genome-wide approaches. Genes and Diseases 1, 75–86 (2014). https://doi.org/10.1016/j.gendis.2014.07.002

    Article  PubMed  PubMed Central  Google Scholar 

  56. J. Califano, W.H. Westra, G. Meininger, R. Corio, W.M. Koch, D. Sidransky, Genetic progression and clonal relationship of recurrent premalignant head and neck lesions. Clin. Cancer Res. 6, 347–352 (2000)

    CAS  PubMed  Google Scholar 

  57. S.I. Pai, W.H. Westra, Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment. Annu. Rev. Pathol. 4, 49–70 (2009). https://doi.org/10.1146/annurev.pathol.4.110807.092158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. C. Jin, Y. Jin, J. Wennerberg, J. Åkervall, B. Grenthe, N. Mandahl, S. Heim, F. Mitelman, F. Mertens, Clonal chromosome aberrations accumulate with age in upper aerodigestive tract mucosa. Mut. Res. - Fundamental and Molecular Mechanisms of Mutagenesis 374, 63–72 (1997). https://doi.org/10.1016/S0027-5107(96)00219-9

    Article  CAS  PubMed  Google Scholar 

  59. E.M. O’Regan, M.E. Toner, P.C. Smyth, S.P. Finn, C. Timon, S. Cahill, R. Flavin, J.J. O’Leary, O. Sheils, Distinct array comparative genomic hybridization profiles in oral squamous cell carcinoma occurring in young patients. Head Neck 28, 330–338 (2006). https://doi.org/10.1002/hed.20354

    Article  PubMed  Google Scholar 

  60. M.D. Ryser, W.T. Lee, N.E. Readyz, K.Z. Leder, J. Foo, Related head and neck cancer : A multi-scale modeling approach. Cancer Res. 76, 7078–7088 (2016). https://doi.org/10.1158/0008-5472.CAN-16-1054.Quantifying

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. J.K. Field, V. Zoumpourlis, D.A. Spandidos, A.S. Jones, P53 expression and mutations in squamous cell carcinoma of the head and neck: expression correlates with the patients’ use of tobacco and alcohol. Cancer Detect. Prev. 18, 197–208 (1994)

    CAS  PubMed  Google Scholar 

  62. J.A. Brennan, J.O. Boyle, W.M. Koch, S.N. Goodman, R.H. Hruban, Y.J. Eby, M.J. Couch, A.A. Forastiere, D. Sidransky, Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 332, 712–717 (1995). https://doi.org/10.1056/nejm199503163321104

    Article  CAS  PubMed  Google Scholar 

  63. J.K. Field, Z.P. Pavelic, D.A. Spandidos, P.J. Stambrook, A.S. Jones, J.L. Gluckman, The role of the P53 tumor suppressor gene in squamous cell carcinoma of the head and neck. Arch. Otolaryngol. - Head and Neck Surgery 119, 1118–1122 (1993). https://doi.org/10.1001/archotol.1993.01880220064009

    Article  CAS  PubMed  Google Scholar 

  64. M.L. Poeta, J. Manola, M.A. Goldwasser, A. Forastiere, N. Benoit, J.A. Califano, J.A. Ridge, J. Goodwin, D. Kenady, J. Saunders, W. Westra, D. Sidransky, W.M. Koch, TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 357, 2552–2561 (2007). https://doi.org/10.1056/nejmoa073770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. A.J. Levine, M. Oren, The first 30 years of P53: growing ever more complex. Nat. Rev. Cancer 9, 749–758 (2009). https://doi.org/10.1038/nrc2723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. D. Bergamaschi, M. Gasco, L. Hiller, A. Sullivan, N. Syed, G. Trigiante, I. Yulug, M. Merlano, G. Numico, A. Comino, M. Attard, O. Reelfs, B. Gusterson, A.K. Bell, V. Heath, M. Tavassoli, P.J. Farrell, P. Smith, X. Lu, T. Crook, P53 Polymorphism influences response in cancer chemotherapy via modulation of P73-DEPENDENT apoptosis. Cancer Cell 3, 387–402 (2003). https://doi.org/10.1016/S1535-6108(03)00079-5

    Article  CAS  PubMed  Google Scholar 

  67. W.M. Koch, J.A. Brennan, M. Zahurak, S.N. Goodman, W.H. Westra, D. Schwab, G.H. Yoo, D.J. Lee, A.A. Forastiere, D. Sidransky, P53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma. J. Natl. Cancer Inst. 88, 1580–1586 (1996). https://doi.org/10.1093/jnci/88.21.1580

    Article  CAS  PubMed  Google Scholar 

  68. J. Gugić, P. Strojan, Squamous cell carcinoma of the head and neck in the elderly. Rep. Pract. Oncol. Radiother. 18, 16–25 (2013). https://doi.org/10.1016/j.rpor.2012.07.014

    Article  Google Scholar 

  69. C.R. Pickering, J. Zhang, D.M. Neskey, M. Zhao, S.A. Jasser, J. Wang, A. Ward, C.J. Tsai, M.V.O. Alves, J.H. Zhou, J. Drummond, A.K. El-Naggar, R. Gibbs, J.N. Weinstein, D.A. Wheeler, J. Wang, M.J. Frederick, J.N. Myers, Squamous cell carcinoma of the oral tongue in young non-smokers is genomically similar to tumors in older smokers. Clin. Cancer Res. 20, 3842–3848 (2014). https://doi.org/10.1158/1078-0432.CCR-14-0565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. A.M.B. De Paula, L.R. Souza, L.C. Farias, G.T.B. Corrêa, C.A.C. Fraga, N.B. Eleutério, A.C.O. Silveira, F.B.G. Santos, D.S. Haikal, A.L.S. Guimarães, R.S. Gomez, Analysis of 724 cases of primary head and neck squamous cell carcinoma (HNSCC) with a focus on young patients and p53 immunolocalization. Oral Oncol. 45, 777–782 (2009). https://doi.org/10.1016/j.oraloncology.2008.11.015

    Article  CAS  PubMed  Google Scholar 

  71. R.S.R. Adduri, V. Kotapalli, N.A. Gupta, S. Gowrishankar, M. Srinivasulu, M.M. Ali, S. Rao, S.G. Uppin, U.K. Nayak, S. Dhagam, M.V. Chigurupati, M.D. Bashyam, P53 nuclear stabilization is associated with fhit loss and younger age of onset in squamous cell carcinoma of oral tongue. BMC Clin. Pathol. 14, 37 (2014). https://doi.org/10.1186/1472-6890-14-37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. J. A. Regezi, N. P. Dekker, A. McMillan, V. Ramirez-Amador, A. Meneses-Garcia, L. M. Ruiz-Godoy Rivera, E. Chrysomali, I. O. L. Ng, P53, P21, Rb, and MDM2 proteins in tongue carcinoma from patients < 35 versus > 75 Years. Oral Oncol. 35, 379–383 (1999). https://doi.org/10.1016/S1368-8375(98)00126-2.

  73. W. Gawȩcki, M. Kostrzewska-Poczekaj, M. Gajȩcka, P. Milecki, K. Szyfter, W. Szyfter, The role of genetic factor in etiopathogenesis of squamous cell carcinoma of the head and neck in young adults. Eur. Arch. Otorhinolaryngol. 264, 1459–1465 (2007). https://doi.org/10.1007/s00405-007-0386-x

    Article  PubMed  Google Scholar 

  74. M. Gajecka, M. Rydzanicz, R. Jaskula-Sztul, M. Kujawski, W. Szyfter, K. Szyfter, CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1 and GSTT1 polymorphisms or their combinations are associated with the increased risk of the laryngeal squamous cell carcinoma. Mut. Res. - Fundamental and Molecular Mechanisms of Mutagenesis. 574, 112–123 (2005). https://doi.org/10.1016/j.mrfmmm.2005.01.027

    Article  CAS  PubMed  Google Scholar 

  75. M. Ünal, L. Tamer, N. Aras Ateş, Y. Akbaş, Y. S. Pata, Y. Vayisoǧlu, B. Ercan, K. Görür, U. Atik, Glutathione S-Transferase M1, T1, and P1 gene polymorphism in laryngeal squamous cell carcinoma. Am. J. Otolaryngol. - Head and Neck Medicine and Surgery 25, 318–322 (2004). https://doi.org/10.1016/j.amjoto.2004.04.003.

  76. C.J. Liu, C.S. Chang, M.T. Lui, C.W. Dang, Y.H. Shih, K.W. Chang, Association of GST genotypes with age of onset and lymph node metastasis in oral squamous cell carcinoma. J. Oral Pathol. Med. 34, 473–477 (2005). https://doi.org/10.1111/j.1600-0714.2005.00345.x

    Article  PubMed  Google Scholar 

  77. X. Zhu, F. Zhang, W. Zhang, J. He, Y. Zhao, X. Chen, Prognostic role of epidermal growth factor receptor in head and neck cancer: a meta-analysis. J. Surg. Oncol. 108, 387–397 (2013). https://doi.org/10.1002/jso.23406

    Article  PubMed  Google Scholar 

  78. V. Costa, L.P. Kowalski, C.M. Coutinho-Camillo, M.D. Begnami, V.F. Calsavara, J.I. Neves, E. Kaminagakura, EGFR amplification and expression in oral squamous cell carcinoma in young adults. Int. J. Oral Maxillofac. Surg. 47, 817–823 (2018). https://doi.org/10.1016/j.ijom.2018.01.002

    Article  CAS  PubMed  Google Scholar 

  79. M. Miranda Galvis, A. R. Santos-Silva, J. Freitas Jardim, F. Paiva Fonseca, M. A. Lopes, O. P. de Almeida, C. A. Lópes Pinto, E. Kaminagakura, I. Sawazaki-Calone, P. M. Speight, L. P. Kowalski, Different patterns of expression of cell cycle control and local invasion-related proteins in oral squamous cell carcinoma affecting young patients. J. Oral Pathol. Med. 47, 32–39 (2018). https://doi.org/10.1111/jop.12601.

  80. G. Ascani, P. Balercia, M. Messi, L. Lupi, G. Goteri, A. Filosa, D. Stramazzotti, T. Pieramici, C. Rubini, Angiogenesis in oral squamous cell carcinoma. Acta otorhinolaryngologica Italica : organo ufficiale della Società italiana di otorinolaringologia e chirurgia cervico-facciale 25, 13–17 (2005)

    CAS  Google Scholar 

  81. S.M. Shivamallappa, N.T. Venkatraman, B. Shreedhar, L. Mohanty, S. Shenoy, Role of angiogenesis in oral squamous cell carcinoma development and metastasis: an immunohistochemical study. Int. J. Oral Sci. 3, 216–224 (2011). https://doi.org/10.4248/IJOS11077

    Article  PubMed  PubMed Central  Google Scholar 

  82. T.G. Benevenuto, C.F.W. Nonaka, L.P. Pinto, L.B. De Souza, Immunohistochemical comparative analysis of cell proliferation and angiogenic index in squamous cell carcinomas of the tongue between young and older patients. Appl. Immunohistochem. Mol. Morphol. 20, 291–297 (2012). https://doi.org/10.1097/PAI.0b013e31823277f6

    Article  PubMed  Google Scholar 

  83. L.R. Teixeira, L.Y. Almeida, R.N. Silva, A.T.M. Mesquita, C.B.N. Colturato, H.A. Silveira, A. Duarte, A. Ribeiro-Silva, J.E. León, Young and elderly oral squamous cell carcinoma patients present similar angiogenic profile and predominance of m2 macrophages: comparative immunohistochemical study. Head Neck 41, 4111–4120 (2019). https://doi.org/10.1002/hed.25954

    Article  PubMed  Google Scholar 

  84. M. Khalili, N. Mahdavi, R. Beheshti, F. Baghai Naini, Immunohistochemical evaluation of angiogenesis and cell proliferation in tongue squamous cell carcinoma. J. Dentistry 12, 846–52 (2015).

  85. S. Meucci, U. Keilholz, I. Tinhofer, O.A. Ebner, Mutational load and mutational patterns in relation to age in head and neck cancer. Oncotarget 7, 69188–69199 (2016). https://doi.org/10.18632/oncotarget.11312

    Article  PubMed  PubMed Central  Google Scholar 

  86. S. Koy, J. Plaschke, H. Luksch, K. Friedrich, E. Kuhlisch, U. Eckelt, R. Martinez, Microsatellite instability and loss of heterozygosity in squamous cell carcinoma of the head and neck. Head Neck 30, 1105–1113 (2008). https://doi.org/10.1002/hed.20857

    Article  PubMed  Google Scholar 

  87. S.W. Coon, A.T. Savera, R.J. Zarbo, M.S. Benninger, G.A. Chase, B.A. Rybicki, D.L. Van Dyke, Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and neck squamous cell carcinoma. Int. J. Cancer 111, 206–212 (2004). https://doi.org/10.1002/ijc.20254

    Article  CAS  PubMed  Google Scholar 

  88. W.M. Koch, M. Lango, D. Sewell, M. Zahurak, D. Sidransky, Head and neck cancer in nonsmokers: a distinct clinical and molecular entity. Laryngoscope 109, 1544–1551 (1999). https://doi.org/10.1097/00005537-199910000-00002

    Article  CAS  PubMed  Google Scholar 

  89. Y.T. Jin, J. Myers, S.T. Tsai, H. Goepfert, J.G. Batsakis, A.K. El-Naggar, Genetic alterations in oral squamous cell carcinoma of young adults. Oral Oncol. 35, 251–256 (1999). https://doi.org/10.1016/S1368-8375(98)00112-2

    Article  CAS  PubMed  Google Scholar 

  90. Y. Wang, J. Irish, C. MacMillan, D. Brown, Y. Xuan, C. Boyington, P. Gullane, S. Kamel-Reid, High frequency of microsatellite instability in young patients with head-and-neck squamous-cell carcinoma: lack of involvement of the mismatch repair genes HMLH1 and HMSH2. Int. J. Cancer 93, 353–360 (2001). https://doi.org/10.1002/ijc.1337

    Article  CAS  PubMed  Google Scholar 

  91. Y. Wang, X. Liu, Y. Li, Target genes of microsatellite sequences in head and neck squamous cell carcinoma: mononucleotide repeats are not detected. Gene 506, 195–201 (2012). https://doi.org/10.1016/j.gene.2012.06.056

    Article  CAS  PubMed  Google Scholar 

  92. M.I. Coolbaugh-Murphy, J. Xu, L.S. Ramagli, B.W. Brown, M.J. Siciliano, Microsatellite instability (MSI) increases with age in normal somatic cells. Mech. Ageing Dev. 126, 1051–1059 (2005). https://doi.org/10.1016/j.mad.2005.06.005

    Article  CAS  PubMed  Google Scholar 

  93. R.M. Castilho, C.H. Squarize, L.O. Almeida, Epigenetic modifications and head and neck cancer: implications for tumor progression and resistance to therapy. Int. J. Mol. Sci. 18, 1506 (2017). https://doi.org/10.3390/ijms18071506

    Article  CAS  PubMed Central  Google Scholar 

  94. D.E. Johnson, B. Burtness, C.R. Leemans, V.W.Y. Lui, J.E. Bauman, J.R. Grandis, Head and neck squamous cell carcinoma. Nat. Rev. Dis. Primers. 6, 92 (2020). https://doi.org/10.1038/s41572-020-00224-3

    Article  PubMed  PubMed Central  Google Scholar 

  95. E.M. O’Regan, M.E. Toner, S.P. Finn, C.Y. Fan, M. Ring, B. Hagmar, C. Timon, P. Smyth, S. Cahill, R. Flavin, O.M. Sheils, J.J. O’Leary, P16INK4A genetic and epigenetic profiles differ in relation to age and site in head and neck squamous cell carcinomas. Hum. Pathol. 39, 452–458 (2008). https://doi.org/10.1016/j.humpath.2007.08.004

    Article  CAS  PubMed  Google Scholar 

  96. J.H. Ng, N.G. Iyer, M.H. Tan, G. Edgren, Changing epidemiology of oral squamous cell carcinoma of the tongue: a global study. Head Neck 39, 297–304 (2017). https://doi.org/10.1002/hed.24589

    Article  PubMed  Google Scholar 

  97. B. R. Campbell, Z. Chen, D. L. Faden, N. Agrawal, R. J. Li, G. J. Hanna, N. G. Iyer, A. Boot, S. G. Rozen, A. L. Vettore, B. Panda, N. M. Krishnan, C. R. Pickering, J. N. Myers, X. Guo, K. A. Lang Kuhs, The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma. Cancer 127, 544–553 (2021). https://doi.org/10.1002/cncr.33309.

  98. A. Paderno, R. Morello, C. Piazza, Tongue carcinoma in young adults: a review of the literature (2018), pp. 175–180

  99. A. Coca-Pelaz, G. B. Halmos, P. Strojan, R. de Bree, P. Bossi, C. R. Bradford, A. Rinaldo, V. Vander Poorten, A. Sanabria, R. P. Takes, A. Ferlito, The role of age in treatment-related adverse events in patients with head and neck cancer: a systematic review. Head and Neck. 41, 2410–2429 (2019). doi: https://doi.org/10.1002/hed.25696.

  100. J.P. Pignon, A. le Maître, E. Maillard, J. Bourhis, Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother. Oncol. 92, 4–14 (2009). https://doi.org/10.1016/j.radonc.2009.04.014

    Article  PubMed  Google Scholar 

  101. R. L. Siegel, K. D. Miller, A. Jemal, Cancer Statistics, 2017. CA: Cancer J. Clin. 67, 7–30 (2017). https://doi.org/10.3322/caac.21387.

  102. C. López-Otín, M.A. Blasco, L. Partridge, M. Serrano, G. Kroemer, The hallmarks of aging. Cell 153, 1194 (2013). https://doi.org/10.1016/j.cell.2013.05.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. B. Bernardes de Jesus, M.A. Blasco, Telomerase at the intersection of cancer and aging. Trends Genet. 29, 513–520 (2013). https://doi.org/10.1016/j.tig.2013.06.007

    Article  CAS  PubMed  Google Scholar 

  104. E.H. Blackburn, E.S. Epel, J. Lin, Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science 350, 1193–1198 (2015). https://doi.org/10.1126/science.aab3389

    Article  CAS  PubMed  Google Scholar 

  105. I.M. Wentzensen, L. Mirabello, R.M. Pfeiffer, S.A. Savage, The association of telomere length and cancer: a meta-analysis. Cancer Epidemiol. Biomark. Prev. 20, 1238–1250 (2011). https://doi.org/10.1158/1055-9965.EPI-11-0005

    Article  CAS  Google Scholar 

  106. P. Boscolo-Rizzo, M.C. Da Mosto, E. Rampazzo, S. Giunco, A. Del Mistro, A. Menegaldo, L. Baboci, M. Mantovani, G. Tirelli, A. De Rossi, Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications. Cancer Metastasis Rev. 35, 457–474 (2016). https://doi.org/10.1007/s10555-016-9633-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. P. Boscolo-Rizzo, E. Rampazzo, E. Perissinotto, M.A. Piano, S. Giunco, L. Baboci, G. Spinato, R. Spinato, G. Tirelli, M.C. Da Mosto, A. Del Mistro, A. De Rossi, Telomere shortening in mucosa surrounding the tumor: biosensor of field cancerization and prognostic marker of mucosal failure in head and neck squamous cell carcinoma. Oral Oncol. 51, 500–507 (2015). https://doi.org/10.1016/j.oraloncology.2015.02.100

    Article  CAS  PubMed  Google Scholar 

  108. J. Aida, T. Izumo, N. Shimomura, K. ichi Nakamura, N. Ishikawa, M. Matsuura, S. S. Poon, M. Fujiwara, M. Sawabe, T. Arai, K. Takubo, Telomere lengths in the oral epithelia with and without carcinoma. Eur. J. Cancer 46, 430–438 (2010). https://doi.org/10.1016/j.ejca.2009.10.018.

  109. J. Aida, T. Kobayashi, T. Saku, M. Yamaguchi, N. Shimomura, K.I. Nakamura, N. Ishikawa, S. Maruyama, J. Cheng, S.S.S. Poon, M. Sawabe, T. Arai, K. Takubo, Short Telomeres in an oral precancerous lesion: Q-FISH analysis of leukoplakia. J. Oral Pathol. Med. 41, 372–378 (2012). https://doi.org/10.1111/j.1600-0714.2011.01120.x

    Article  PubMed  Google Scholar 

  110. Y. Liu, X. li Dong, C. Tian, H. gang Liu, Human Telomerase RNA Component (HTERC) gene amplification detected by fish in precancerous lesions and carcinoma of the larynx. Diagn. Pathol. 7, 34 (2012). https://doi.org/10.1186/1746-1596-7-34.

  111. K.P. Chang, C.I. Wang, C.R. Pickering, Y. Huang, C.N. Tsai, N.M. Tsang, H.K. Kao, M.H. Cheng, J.N. Myers, Prevalence of promoter mutations in the TERT gene in oral cavity squamous cell carcinoma. Head Neck 39, 1131–1137 (2017). https://doi.org/10.1002/hed.24728

    Article  PubMed  Google Scholar 

  112. W. Barczak, W.M. Suchorska, A. Sobecka, K. Bednarowicz, P. Machczynski, P. Golusinski, B. Rubis, M.M. Masternak, W. Golusinski, HTERT C250T promoter mutation and telomere length as a molecular markers of cancer progression in patients with head and neck cancer. Mol. Med. Rep. 16, 441–446 (2017). https://doi.org/10.3892/mmr.2017.6590

    Article  CAS  PubMed  Google Scholar 

  113. D.T. Bau, S.M. Lippman, E. Xu, Y. Gong, J.J. Lee, X. Wu, J. Gu, Short telomere lengths in peripheral blood leukocytes are associated with an increased risk of oral premalignant lesion and oral squamous cell carcinoma. Cancer 119, 4277–4283 (2013). https://doi.org/10.1002/cncr.28367

    Article  PubMed  Google Scholar 

  114. Y. Qu, S. Dang, K. Wu, Y. Shao, Q. Yang, M. Ji, B. Shi, P. Hou, TERT promoter mutations predict worse survival in laryngeal cancer patients. Int. J. Cancer 135, 1008–1010 (2014). https://doi.org/10.1002/ijc.28728

    Article  CAS  PubMed  Google Scholar 

  115. J. Lin, E. Epel, E. Blackburn, Telomeres and lifestyle factors: roles in cellular aging. Mut. Res. - Fundamental and Molecular Mechanisms of Mutagenesis. 730, 85–89 (2012). https://doi.org/10.1016/j.mrfmmm.2011.08.003

    Article  CAS  PubMed  Google Scholar 

  116. J. Raschenberger, B. Kollerits, J. Ritchie, B. Lane, P.A. Kalra, E. Ritz, F. Kronenberg, Association of relative telomere length with progression of chronic kidney disease in two cohorts: effect modification by smoking and diabetes. Sci. Rep. 5, 11887 (2015). https://doi.org/10.1038/srep11887

    Article  PubMed  PubMed Central  Google Scholar 

  117. O.G. Opitz, Y. Suliman, W.C. Hahn, H. Harada, H.E. Blum, A.K. Rustgi, Cyclin D1 overexpression and P53 inactivation immortalize primary oral keratinocytes by a telomerase-independent mechanism. J. Clin. Investig. 108, 725–732 (2001). https://doi.org/10.1172/jci11909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. W. Chen, B.K. Xiao, J.P. Liu, S.M. Chen, Z.Z. Tao, Alternative lengthening of telomeres in HTERT-inhibited laryngeal cancer cells. Cancer Sci. 101, 1769–1776 (2010). https://doi.org/10.1111/j.1349-7006.2010.01611.x

    Article  CAS  PubMed  Google Scholar 

  119. V. Vitelli, P. Falvo, S. G. Nergadze, M. Santagostino, L. Khoriauli, P. Pellanda, G. Bertino, A. Occhini, M. Benazzo, P. Morbini, M. Paulli, C. Porta, E. Giulotto, Telomeric Repeat-CONTAINING RNAs (TERRA) Decrease in squamous cell carcinoma of the head and neck is associated withworsened clinical outcome. Int. J. Mol. Sci. 19, 274 (2018). https://doi.org/10.3390/ijms19010274.

  120. H.H. Chen, C.H. Yu, J.T. Wang, B.Y. Liu, Y.P. Wang, A. Sun, T.C. Tsai, C.P. Chiang, Expression of human telomerase reverse transcriptase (HTERT) protein is significantly associated with the progression, recurrence and prognosis of oral squamous cell carcinoma in Taiwan. Oral Oncol. 43, 122–129 (2007). https://doi.org/10.1016/j.oraloncology.2006.01.011

    Article  CAS  PubMed  Google Scholar 

  121. E. Rampazzo, R. Bertorelle, L. Serra, L. Terrin, C. Candiotto, S. Pucciarelli, P. Del Bianco, D. Nitti, A. De Rossi, Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers. Br. J. Cancer 102, 1300–1305 (2010). https://doi.org/10.1038/sj.bjc.6605644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. D. Tweats, D. A. Eastmond, A. M. Lynch, A. Elhajouji, R. Froetschl, M. Kirsch-Volders, F. Marchetti, K. Masumura, F. Pacchierotti, M. Schuler, Role of Aneuploidy in the Carcinogenic Process: Part 3 of the Report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases. Mut. Res. - Genetic Toxicology and Environmental Mutagenesis 847, 403032 (2019). https://doi.org/10.1016/j.mrgentox.2019.03.005.

  123. P. Castagnola, S. Gandolfo, D. Malacarne, C. Aiello, R. Marino, G. Zoppoli, A. Ballestrero, W. Giaretti, M. Pentenero, DNA aneuploidy relationship with patient age and tobacco smoke in OPMDs/OSCCs. PLoS ONE 12, e0184425 (2017). https://doi.org/10.1371/journal.pone.0184425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. L.G.T. Morris, A.M. Kaufman, Y. Gong, D. Ramaswami, L.A. Walsh, Ş Turcan, S. Eng, K. Kannan, Y. Zou, L. Peng, V.E. Banuchi, P. Paty, Z. Zeng, E. Vakiani, D. Solit, B. Singh, I. Ganly, L. Liau, T.C. Cloughesy, P.S. Mischel, I.K. Mellinghoff, T.A. Chan, Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat. Genet. 45, 253–261 (2013). https://doi.org/10.1038/ng.2538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. K.T. Kim, B.S. Kim, J.H. Kim, Association between FAT1 mutation and overall survival in patients with human papillomavirus-negative head and neck squamous cell carcinoma. Head Neck 38, E2021–E2029 (2016). https://doi.org/10.1002/hed.24372

    Article  PubMed  PubMed Central  Google Scholar 

  126. B. Bottazzi, E. Riboli, A. Mantovani, Aging, inflammation and cancer. Semin. Immunol. 40, 74–82 (2018). https://doi.org/10.1016/j.smim.2018.10.011

    Article  CAS  PubMed  Google Scholar 

  127. E. Bonavita, S. Gentile, M. Rubino, V. Maina, R. Papait, P. Kunderfranco, C. Greco, F. Feruglio, M. Molgora, I. Laface, S. Tartari, A. Doni, F. Pasqualini, E. Barbati, G. Basso, M.R. Galdiero, M. Nebuloni, M. Roncalli, P. Colombo, L. Laghi, J.D. Lambris, S. Jaillon, C. Garlanda, A. Mantovani, PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160, 700–714 (2015). https://doi.org/10.1016/j.cell.2015.01.004

    Article  CAS  PubMed  Google Scholar 

  128. S.S. Jeske, P.J. Schuler, J. Doescher, M.N. Theodoraki, S. Laban, C. Brunner, T.K. Hoffmann, M.C. Wigand, Age-related changes in t lymphocytes of patients with head and neck squamous cell carcinoma. Immunity and Ageing 17, 3 (2020). https://doi.org/10.1186/s12979-020-0174-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. S. Alfieri, S. Cavalieri, L. Licitra, Immunotherapy for recurrent/metastatic head and neck cancer. Curr. Opin. Otolaryngol. Head Neck Surg. 26, 152–156 (2018). https://doi.org/10.1097/MOO.0000000000000448

    Article  PubMed  Google Scholar 

  130. R. L. Ferris, G. Blumenschein, J. Fayette, J. Guigay, A. D. Colevas, L. Licitra, K. Harrington, S. Kasper, E. E. Vokes, C. Even, F. Worden, N. F. Saba, L. C. Iglesias Docampo, R. Haddad, T. Rordorf, N. Kiyota, M. Tahara, M. Monga, M. Lynch, W. J. Geese, J. Kopit, J. W. Shaw, M. L. Gillison, Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Eng. J. Med. 375, 1856–1867 (2016). https://doi.org/10.1056/nejmoa1602252.

  131. T.Y. Seiwert, B. Burtness, R. Mehra, J. Weiss, R. Berger, J.P. Eder, K. Heath, T. McClanahan, J. Lunceford, C. Gause, J.D. Cheng, L.Q. Chow, 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. 17, 956–965 (2016). https://doi.org/10.1016/S1470-2045(16)30066-3

    Article  CAS  PubMed  Google Scholar 

  132. D. Lenouvel, M.Á. González-Moles, I. Ruiz-Ávila, L. Gonzalez-Ruiz, I. Gonzalez-Ruiz, P. Ramos-García, Prognostic and clinicopathological significance of PD-L1 overexpression in oral squamous cell carcinoma: a systematic review and comprehensive meta-analysis. Oral Oncol. 106, 104722 (2020). https://doi.org/10.1016/j.oraloncology.2020.104722

    Article  CAS  PubMed  Google Scholar 

  133. N. Ngamphaiboon, T. Chureemas, T. Siripoon, L. Arsa, N. Trachu, C. Jiarpinitnun, P. Pattaranutaporn, E. Sirachainan, N. Larbcharoensub, Characteristics and impact of programmed death-ligand 1 expression, CD8+ tumor-infiltrating lymphocytes, and P16 status in head and neck squamous cell carcinoma. Med. Oncol. 36, 1–10 (2019). https://doi.org/10.1007/s12032-018-1241-1

    Article  Google Scholar 

  134. G.J. Hanna, S.B. Woo, Y.Y. Li, J.A. Barletta, P.S. Hammerman, J.H. Lorch, Tumor PD-L1 expression is associated with improved survival and lower recurrence risk in young women with oral cavity squamous cell carcinoma. Int. J. Oral Maxillofac. Surg. 47, 568–577 (2018). https://doi.org/10.1016/j.ijom.2017.09.006

    Article  CAS  PubMed  Google Scholar 

  135. P.A. Jones, S.B. Baylin, The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428 (2002). https://doi.org/10.1038/nrg816

    Article  CAS  PubMed  Google Scholar 

  136. B.H. Chen, R.E. Marioni, E. Colicino, M.J. Peters, C.K. Ward-Caviness, P.C. Tsai, N.S. Roetker, A.C. Just, E.W. Demerath, W. Guan, J. Bressler, M. Fornage, S. Studenski, A.R. Vandiver, A.Z. Moore, T. Tanaka, D.P. Kiel, L. Liang, P. Vokonas, J. Schwartz, K.L. Lunetta, J.M. Murabito, S. Bandinelli, D.G. Hernandez, D. Melzer, M. Nalls, L.C. Pilling, T.R. Price, A.B. Singleton, C. Gieger, R. Holle, A. Kretschmer, F. Kronenberg, S. Kunze, J. Linseisen, C. Meisinger, W. Rathmann, M. Waldenberger, P.M. Visscher, S. Shah, N.R. Wray, A.F. McRae, O.H. Franco, A. Hofman, A.G. Uitterlinden, D. Absher, T. Assimes, M.E. Levine, A.T. Lu, P.S. Tsao, L. Hou, J.A.E. Manson, C.L. Carty, A.Z. LaCroix, A.P. Reiner, T.D. Spector, A.P. Feinberg, D. Levy, A. Baccarelli, J. van Meurs, J.T. Bell, A. Peters, I.J. Deary, J.S. Pankow, L. Ferrucci, S. Horvath, DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging 8, 1844–1865 (2016). https://doi.org/10.18632/aging.101020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. S. Horvath, K. Raj, DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018). https://doi.org/10.1038/s41576-018-0004-3

    Article  CAS  PubMed  Google Scholar 

  138. M. Yu, W.D. Hazelton, G.E. Luebeck, W.M. Grady, Epigenetic aging: more than just a clock when it comes to cancer. Cancer Res. 80, 367–374 (2020). https://doi.org/10.1158/0008-5472.CAN-19-0924

    Article  CAS  Google Scholar 

  139. Y. Zheng, B.T. Joyce, E. Colicino, L. Liu, W. Zhang, Q. Dai, M.J. Shrubsole, W.A. Kibbe, T. Gao, Z. Zhang, N. Jafari, P. Vokonas, J. Schwartz, A.A. Baccarelli, L. Hou, Blood epigenetic age may predict cancer incidence and mortality. EBioMedicine 5, 68–73 (2016). https://doi.org/10.1016/j.ebiom.2016.02.008

    Article  PubMed  PubMed Central  Google Scholar 

  140. C. Huang, L. Chen, S. R. Savage, R. V. Eguez, Y. Dou, Y. Li, F. da Veiga Leprevost, E. J. Jaehnig, J. T. Lei, B. Wen, M. Schnaubelt, K. Krug, X. Song, M. Cieślik, H. Y. Chang, M. A. Wyczalkowski, K. Li, A. Colaprico, Q. K. Li, D. J. Clark, Y. Hu, L. Cao, J. Pan, Y. Wang, K. C. Cho, Z. Shi, Y. Liao, W. Jiang, M. Anurag, J. Ji, S. Yoo, D. C. Zhou, W. W. Liang, M. Wendl, P. Vats, S. A. Carr, D. R. Mani, Z. Zhang, J. Qian, X. S. Chen, A. R. Pico, P. Wang, A. M. Chinnaiyan, K. A. Ketchum, C. R. Kinsinger, A. I. Robles, E. An, T. Hiltke, M. Mesri, M. Thiagarajan, A. M. Weaver, A. G. Sikora, J. Lubiński, M. Wierzbicka, M. Wiznerowicz, S. Satpathy, M. A. Gillette, G. Miles, M. J. Ellis, G. S. Omenn, H. Rodriguez, E. S. Boja, S. M. Dhanasekaran, L. Ding, A. I. Nesvizhskii, A. K. El-Naggar, D. W. Chan, H. Zhang, B. Zhang, A. Agarwal, M. L. Anderson, S. C. Avanessian, D. Avtonomov, O. F. Bathe, C. Birger, M. J. Birrer, L. Blumenberg, W. E. Bocik, U. Borate, M. Borucki, M. C. Burke, S. Cai, A. P. Calinawan, S. Cerda, A. Charamut, L. S. Chen, S. Chowdhury, K. R. Clauser, H. Culpepper, T. Czernicki, F. D’Angelo, J. Day, S. De Young, E. Demir, F. Ding, M. J. Domagalski, J. C. Dort, B. Druker, E. Duffy, M. Dyer, N. J. Edwards, K. Elburn, T. S. Ermakova, D. Fenyo, R. Ferrarotto, A. Francis, S. Gabriel, L. Garofano, Y. Geffen, G. Getz, C. A. Goldthwaite, L. I. Hannick, P. Hariharan, D. N. Hayes, D. Heiman, B. Hindenach, K. A. Hoadley, G. Hostetter, M. Hyrcza, S. D. Jewell, C. D. Jones, M. H. Kane, A. Karz, R. B. Kothadia, A. Krek, C. Kumar-Sinha, T. Liu, H. Liu, W. Ma, E. Malc, A. Malovannaya, S. Mareedu, S. P. Markey, A. Marrero-Oliveras, N. Maunganidze, J. E. McDermott, P. B. McGarvey, J. McGee, P. Mieczkowski, S. Migliozzi, R. Montgomery, C. J. Newton, U. Ozbek, A. G. Paulovich, S. H. Payne, D. D. Pazardzhikliev, A. M. Perou, F. Petralia, L. Petrenko, P. D. Piehowski, D. Placantonakis, L. Polonskaya, E. V. Ponomareva, O. Potapova, L. Qi, N. Qu, S. Ramkissoon, B. Reva, S. Richey, K. Robinson, N. Roche, K. Rodland, D. C. Rohrer, D. Rykunov, E. E. Schadt, Y. Shi, Y. Shutack, S. Singh, T. Skelly, R. Smith, L. J. Sokoll, J. Stawicki, S. E. Stein, J. Suh, W. Szopa, D. Tabor, D. Tan, D. Tansil, G. C. Teo, R. R. Thangudu, C. Tognon, E. Traer, S. Tsang, J. Tyner, K. S. Um, D. R. Valley, L. V. Vasilev, N. Vatanian, U. Velvulou, M. Vernon, T. F. Westbrook, J. R. Whiteaker, Y. Wu, M. Xu, L. Yao, X. Yi, F. Yu, K. Zaalishvili, Y. Zakhartsev, R. Zelt, G. Zhao, J. Zhu, Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma. Cancer Cell 39, 361–379.e16 (2021). https://doi.org/10.1016/j.ccell.2020.12.007.

  141. G. Marioni, A. Staffieri, E. Manzato, G. Ralli, M. Lionello, L. Giacomelli, V. Prosenikliev, R. Marchese-Ragona, A. Busnardo, F. Bolzetta, S. Blandamura, A higher CD105-assessed microvessel density and worse prognosis in elderly patients with laryngeal carcinoma. Arch. Otolaryngol. Head Neck Surg. 137, 175–180 (2011). https://doi.org/10.1001/archoto.2010.244

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700RB, Groningen, The Netherlands

    Martine Froukje van der Kamp, Gyorgy Bela Halmos, Boudewijn Evert Christiaan Plaat & Cornelia Johanna Verhoeven

  2. European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Victor Guryev

  3. Department of Pharmacy, Analytical Biochemistry, University of Groningen, Groningen, The Netherlands

    Peter Laszlo Horvatovich

  4. Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Ed Schuuring & Bert van der Vegt

  5. Department of Otorhinolaryngology and Head and Neck Surgery, Haaglanden Medical Center, The Hague, The Netherlands

    Bernardus Franciscus Augustinus Maria van der Laan

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  1. Martine Froukje van der Kamp
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Contributions

M.F. van der Kamp – acquisition, analysis and interpretation of literature data, drafting the manuscript.

C.J. Verhoeven—concept of design, acquisition, analysis and interpretation of literature data, drafting the manuscript.

G.B. Halmos – concept of design, interpretation of literature data, critical revision the manuscript.

B.E.C. Plaat—interpretation of literature data, critical revision the manuscript.

B.F.A.M. van der Laan—critical revision the manuscript.

P.L. Horvatovich—concept of design, critical revision the manuscript.

V. Guryev—critical revision the manuscript.

E. Schuuring—critical revision the manuscript.

B. van der Vegt—concept of design, critical revision the manuscript.

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Correspondence to Martine Froukje van der Kamp.

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Appendix 1. Literature search

Appendix 1. Literature search

Given the broad scope and aim of this review, an open literature search rather than a systematic literature search was conducted in the database Pubmed/Medline.

Multiple searches using variations of Mesh terms with the following key elements: head and neck squamous cell carcinoma (HNSCC), ageing, physiopathology, and tumor biology. For HNSCC, the Mesh terms included: head and neck cancer, laryngeal carcinoma, laryngeal cancer, LSCC, hypopharyngeal carcinoma, hypopharyngeal cancer, oropharyngeal carcinoma, oropharyngeal cancer, OSCC, tongue carcinoma, and tongue cancer. For physiopathology, the Mesh terms included: physiopathology, tumor biology, molecular biology, molecular pathway, cellular ageing, cellular senescence, inheritance, inherited, familial tumors, and familial cancer syndromes. For ageing, the Mesh terms included: age, ag(e)ing, age-related, age-dependent, young, elderly, old.

Search results were screened on title and abstract to determine if ageing was the main topic or a factor significantly correlating with a pathway or biological marker. If this was the case, manuscripts were selected for full reviewing. Furthermore, to find more potential articles that were not identified by the literature search, citations of relevant articles were screened and when matching the scope of this article, included.

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van der Kamp, M.F., Halmos, G.B., Guryev, V. et al. Age-specific oncogenic pathways in head and neck squamous cell carcinoma - are elderly a different subcategory?. Cell Oncol. 45, 1–18 (2022). https://doi.org/10.1007/s13402-021-00655-4

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