Skip to main content

Advertisement

Log in

Molecular pathogenesis of head and neck squamous cell carcinoma

  • Head and Neck Oncology
  • Published:
European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

Head and neck squamous cell carcinoma (HNSCC) represents 6% of all cancers. The overall 5-year survival rate for patients with this type of cancer is among the lowest of the major cancer types and has not improved dramatically during the last decade. The pathological staging, in particular the nodal stage, is the most important factor in HNSCC. The lack of progress in head and neck oncology emphasizes the importance of molecular genetic studies to define alterations that may correlate with tumor behavior. The molecular alterations observed in HNSCC are mainly due to oncogene activation and tumor suppressor gene inactivation, leading to deregulation of cell proliferation. These alterations include gene amplification and overexpression of oncogenes such as ras, myc, EGFR and cyclin D1, and mutations and deletions leading to p16 and TP53 tumor suppressor genes inactivation. This article reviews the molecular changes commonly observed in HNSCC. The biological function of these markers and the potential clinical application are discussed. Advances in the understanding of the molecular basis of HNSCC will help in the identification of new molecular markers that could be used for a more accurate diagnosis and assessment of prognosis and may open the way for novel approaches to treatment and prevention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.

Similar content being viewed by others

References

  1. Ah-See KW, Cooke TG, Pickford IR, Soutar D, Balmain A (1994) An allelotype of squamous cell carcinoma of the head and neck using microsatellite markers. Cancer Res 54: 1617–1621

    CAS  PubMed  Google Scholar 

  2. Akervall JA, Michalides RJ, Mineta H, Balm A, Borg A, Dictor MR, Lin Y, Loftus B, Mertens F, Wennerberg JP (1997) Amplification of cyclin D1 in squamous cell carcinoma of the head and neck and the progression value of chromosomal abnormalities and cyclin D1 overexpression. Cancer 79: 380–389

    CAS  PubMed  Google Scholar 

  3. Bellacosa A, Almadori G, Cavallo S, Cadoni G, Galli J, Ferrandina G, Scambia G, Neri G (1996) Cyclin D1 gene amplification in human laryngeal squamous cell carcinomas: prognostic significance and clinical implications. Clin Cancer Res 2: 175–180

    CAS  PubMed  Google Scholar 

  4. Belbin TJ, Singh B, Barber I, Socci N, Wenig B, Smith R, Prystowsky MB, Childs G (2002) Molecular classification of head and neck squamous cell carcinoma using cDNA microarrays. Cancer Res 62: 1184–1190

    CAS  PubMed  Google Scholar 

  5. Berenson JR, Yang J, Mickel RA (1989) Frequent amplification of the bcl-1 locus in head and neck squamous cell carcinomas. Oncogene 4: 1111–1116

    Google Scholar 

  6. Bouchard C, Stahler P, Eilers M (1998) Control of cell proliferation by Myc. Trends Cell Biol 8: 202–206

    Article  CAS  PubMed  Google Scholar 

  7. Brennan JA, Mao L, Hruban RH, Boyle JO, Eby YJ, Koch WM, Goodman SN, Sidransky D (1995) Molecular assessment of histopathological staining in squamous-cell carcinoma of the head and neck. N Engl J Med 332: 429–435

    CAS  PubMed  Google Scholar 

  8. Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, Corio R, Lee D, Greenberg B, Koch W, Sidransky D (1996) Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 56: 2488–2492

    CAS  PubMed  Google Scholar 

  9. Caminero MJ, Nunez F, Suarez C, Ablanedo P, Riera JR, Dominguez F (1996) Detection of p53 protein in oropharyngeal carcinoma. Prognostic implications. Arch Otolaryngol Head Neck Surg 122: 769–772

    Google Scholar 

  10. Dassonville O, Formento JL, Francoual M, Ramaioli A, Santini J, Schneider M, Demard F, Milano G (1993) Expression of epidermal growth factor receptor and survival in upper aerodigestive tract. J Clin Oncol 11: 1873–1878

    CAS  PubMed  Google Scholar 

  11. Erber R, Conradt C, Homann N, Enders C, Finckh M, Dietz A, Weidauer H, Bosch FX (1998) TP53 DNA contact mutations are selectively associated with allelic loss and have a strong clinical impact in head and neck cancer. Oncogene 16: 1671–1679

    Article  CAS  PubMed  Google Scholar 

  12. Field JK, Spandidos DA, Stell PM, Vaughan ED, Evan GI, Moore JP (1989) Elevated expression of the c-myc oncoprotein correlates with poor prognosis in head and neck squamous cell carcinoma. Oncogene 4: 1463–1468

    CAS  PubMed  Google Scholar 

  13. Fracchiolla NS, Pruneri G, Pignataro L, Carboni N, Capaccio P, Boletini A, Buffa R, Neri A (1997) Molecular and immunohistochemical analysis of the bcl-1/cyclin D1 gene in laryngeal squamous cell carcinomas: correlation of protein expression with lymph node metastases and advanced clinical stage. Cancer 79: 1114–1121

    Article  CAS  PubMed  Google Scholar 

  14. Frank JL, Bur ME, Garb JL, Kay S, Ware JL, Sismanis A, Neifeld JP (1994) p53 tumor suppressor oncogene expression in squamous cell carcinoma of the hypopharynx. Cancer 73: 181–186

    CAS  PubMed  Google Scholar 

  15. Friedman M, Grey P, Venkatesan TK, Bloch I, Chawla P, Caldarelli DD, Coon JS (1997) Prognostic significance of Bcl-2 expression in localized squamous cell carcinoma of the head and neck. Ann Otol Rhinol Laryngol 106: 445–450

    Google Scholar 

  16. Gallo O, Boddi V, Calzolari A, Simonetti L, Trovati M, Bianchi S (1996) bcl-2 protein expression correlates with recurrence and survival in early stage head and neck cancer treated by radiotherapy. Clin Cancer Res 2: 261–267

    CAS  PubMed  Google Scholar 

  17. Gonzalez MV, Pello MF, Lopez-Larrea C, Suarez C, Menendez MJ, Coto E (1997) Deletion and methylation of the tumour suppressor gene p16/CDKN2 in primary head and neck squamous cell carcinoma. J Clin Pathol 50: 509–512

    CAS  PubMed  Google Scholar 

  18. Grandis JR, Tweardy DJ (1993) Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 53: 3579–3584

    CAS  PubMed  Google Scholar 

  19. Hackel PO, Zwick E, Prenzel N, Ullrich A (1999) Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr Opin Cell Biol 11: 184–189

    CAS  PubMed  Google Scholar 

  20. Hirvikoski P, Kumpulainen EJ, Virtaniemi JA, Helin HJ, Rantala I, Johansson RT, Juhola M, Kosma VM (1998) Cytoplasmic accumulation of alpha-catenin is associated with aggressive features in laryngeal squamous-cell carcinoma. Int J Cancer 79: 546–550

    Article  CAS  PubMed  Google Scholar 

  21. Hirvikoski P, Kumpulainen E, Virtaniemi JA, Pirinen R, Salmi L, Halonen P, Johansson R, Kosma VM (1999) Enhanced apoptosis correlates with poor survival in patients with laryngeal cancer but not with cell proliferation, bcl-2 or p53 expression. Eur J Cancer 35: 231–237

    Article  CAS  PubMed  Google Scholar 

  22. Hoffman HT, Karnell LH, Funk GF, Robinson RA, Menck HR (1998) The National Cancer Data Base report on cancer of the head and neck. Arch Otolaryngol Head Neck Surg 124: 951–962

    CAS  PubMed  Google Scholar 

  23. Hotz MA, Bosq J, Zbaeren P, Reed J, Schwab G, Krajewski S, Brousset P, Borner MM (1999) Spontaneous apoptosis and the expression of p53 and Bcl-2 family proteins in locally advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 125: 417–422

    Google Scholar 

  24. Jin YT, Kayser S, Kemp BL, Ordonez NG, Tucker SL, Clayman GL, Goepfert H, Luna MA, Batsakis JG, El-Naggar AK (1998) The prognostic significance of the biomarkers p21WAF1(CIP1), PR1WAF1(CIP1), p53, and bcl-2 in laryngeal squamous cell carcinoma. Cancer 82: 2159–2165

    CAS  PubMed  Google Scholar 

  25. Koch WM, Brennan JA, Zahurak M, Goodman SN, Westra WH, Schwab D, Yoo GH, Lee DJ, Forastiere AA, Sidransky D (1996) p53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma. J Natl Cancer Inst 88: 1580–1586

    CAS  PubMed  Google Scholar 

  26. Kropveld A, Rozenmuller EH, Leppers FG, Scheidel KC, de Weger RA, Koole R, Hordijk GJ, Slootweg PJ, Tilanus MG (1999) Sequencing analysis of RNA and DNA of exons 1 through 11 shows p53 gene alterations to be present in almost 100% of head and neck squamous cell cancers. Lab Invest 79: 347–353

    CAS  PubMed  Google Scholar 

  27. Kyomoto R, Kumazawa H, Toda Y, Sakaida N, Okamura A, Iwanaga M, Shintaku M, Yamashita T, Hiai H, Fukumoto M (1997) Cyclin-D1-gene amplification is a more potent prognostic factor than its protein over-expression in human head-and-neck squamous-cell carcinoma. Int J Cancer 74: 576–581

    Article  CAS  PubMed  Google Scholar 

  28. Leonard JH, Kearsley JH, Chevenix-Trench G, Hayward NK (1991) Analysis of gene amplification in head-and-neck squamous-cell carcinoma. Int J Cancer 48: 511–515

    CAS  PubMed  Google Scholar 

  29. Maurizi M, Almadori G, Ferrandina G, Distefano M, Romanini ME, Cadoni G, Benedetti-Panici P, Paludetti G, Scambia G, Mancuso S (1996) Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. Br J Cancer 74: 1243–1257

    Google Scholar 

  30. Meredith SD, Levine PA, Burns JA, Gaffey MJ, Boyd JC, Weiss LM, Erickson NL, Williams ME (1995) Chromosome 11q13 amplification in head and neck squamous cell carcinoma. Association with poor prognosis. Arch Otolaryngol Head Neck Surg 121: 790–794

    CAS  PubMed  Google Scholar 

  31. Michalides RJ, van Veelen NM, Kristel PM, Hart AA, Loftus BM, Hilgers FJ, Balm AJ (1997) Overexpression of cyclin D1 indicates a poor prognosis in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 123: 497–502

    Google Scholar 

  32. Miracca EC, Kowalski LP, Nagai MA (1999) High prevalence of p16 genetic alterations in head and neck tumours. Br J Cancer 81: 677–683

    Article  CAS  PubMed  Google Scholar 

  33. Miyaguchi M, Olofsson J, Hellquist HB (1990) Expression of epidermal growth factor receptor in laryngeal dysplasia and carcinoma. Acta Otolaryngol 110: 309–313

    Google Scholar 

  34. Muller D, Millon R, Velten M, Bronner G, Jung G, Engelmann A, Flesch H, Eber M, Methlin G, Abecassis J (1997) Amplification of 11q13 DNA markers in head and neck squamous cell carcinomas: correlation with clinical outcome. Eur J Cancer 33: 2203–2210

    Article  CAS  PubMed  Google Scholar 

  35. Oh Y, Mao L (1997) Biomarkers in head and neck carcinoma. Curr Opin Oncol 9: 247–256

    CAS  PubMed  Google Scholar 

  36. Pignataro L, Pruneri G, Carboni N, Capaccio P, Cesana BM, Neri A, Buffa R (1998) Clinical relevance of cyclin D1 protein overexpression in laryngeal squamous cell carcinoma. J Clin Oncol 16: 3069–3077

    CAS  PubMed  Google Scholar 

  37. Porter MJ, Field JK, Leung SF, Lo D, Lee JC, Spandidos DA, van Hasselt CA (1994) The detection of the c-myc and ras oncogenes in nasopharyngeal carcinoma by immunohistochemistry. Acta Otolaryngol 114: 105–109

    Google Scholar 

  38. Pruneri G, Pignataro L, Carboni N, Ronchetti D, Cesana BM, Ottaviani A, Neri A, Buffa R (1998) Clinical relevance of p53 and bcl-2 protein over-expression in laryngeal squamous-cell carcinoma. Int J Cancer 79: 263–268

    Article  CAS  PubMed  Google Scholar 

  39. Reed AL, Califano J, Cairns P, Westra WH, Jones RM, Koch W, Ahrendt S, Eby Y, Sewell D, Nawroz H, Bartek J, Sidransky D (1996) High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res 56: 3630–3633

    CAS  PubMed  Google Scholar 

  40. Rodrigo JP, Lazo PS, Ramos A, Alvarez I, Suarez C (1996) MYC amplification in squamous cell carcinomas of the head and neck. Arch Otolaryngol Head Neck Surg 122: 504–507

    Google Scholar 

  41. Rowley H, Roland NJ, Helliwell TR, Caslin A, Kinsella AR, Jones AS (1998) p53 protein expression in tumours from head and neck subsites, larynx and hypopharynx, and differences in relationship to survival. Clin Otolaryngol 23: 57–62

    Google Scholar 

  42. Saranath D, Chang SE, Bhoite LT, Panchal RG, Kerr IB, Mehta AR, Johnson NW, Deo MG (1991) High frequency mutation in codons 12 and 61 of H-ras oncogene in chewing tobacco-related human oral carcinoma in India. Cancer Res 63: 573–578

    CAS  Google Scholar 

  43. Saunders ME, MacKenzie R, Shipman R, Fransen E, Gilbert R, Jordan RC (1999) Patterns of p53 gene mutations in head and neck cancer: full-length gene sequencing and results of primary radiotherapy. Clin Cancer Res 5: 2455–2463

    CAS  PubMed  Google Scholar 

  44. Schipper JH, Frixen UH, Behrens J, Unger A, Jahnke K, Birchmeier W (1991) E-cadherin expression in squamous cell carcinomas of the head and neck: inverse correlation with tumor dedifferentiation and lymph nodes metastasis. Cancer Res 51: 6328–6337

    CAS  PubMed  Google Scholar 

  45. Shin DM, Lee JS, Lippman SM, Lee JJ, Tu ZN, Choi G, Heyne K, Shin HJ, Ro JY, Goepfert H, Hong WK, Hittelman WN (1996) p53 expressions: predicting recurrence and second primary tumors in head and neck squamous cell carcinoma. J Natl Cancer Inst 88: 519–529

    CAS  PubMed  Google Scholar 

  46. Sionov RV, Haupt Y (1999) The cellular response to p53: the decision between life and death. Oncogene 18: 6145–6157

    Article  PubMed  Google Scholar 

  47. Somers KD, Schechter GL (1992) Genetic alterations in head and neck cancer. Otolaryngol Clin North Am 25: 1065–1071

    CAS  PubMed  Google Scholar 

  48. Spafford MF, Koeppe J, Pan Z, Archer PG, Meyers AD, Franklin WA (1996) Correlation of tumor markers p53, bcl-2, CD34, CD44H, CD44v6, and Ki-67 with survival and metastasis in laryngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 122: 627–632

    Google Scholar 

  49. van Aken E, De Wever O, Correia da Rocha AS, Mareel M (2001) Defective E-cadherin/catenin complexes in human cancer. Virchows Arch 439: 725–751

    PubMed  Google Scholar 

  50. van der Riet P, Nawroz H, Hruban RH, Corio R, Tokino K, Koch W, Sidransky D (1994) Frequent loss of chromosome 9p21–22 early in head and neck cancer progression. Cancer Res 54: 1156–1158

    PubMed  Google Scholar 

  51. Wallace-Brodeur RR, Lowe SW (1999) Clinical implications of p53 mutations. Cell Mol Life Sci 55: 64–75

    Article  CAS  PubMed  Google Scholar 

  52. Wen QH, Miwa T, Yoshizaki T, Nagayama I, Furukawa M, Nishijima H (1996) Prognostic value of EGFR and TGF-alpha in early laryngeal cancer treated with radiotherapy. Laryngoscope 106: 884–888

    Google Scholar 

  53. Xie X, Clausen OP, De Angelis P, Boysen M (1999) The prognostic value of spontaneous apoptosis, Bax, Bcl-2, and p53 in oral squamous cell carcinoma of the tongue. Cancer 86: 913–920

    CAS  PubMed  Google Scholar 

  54. Yarbrough WG, Shores C, Witsell DL, Weissler MC, Fidler ME, Gilmer TM (1994) ras mutations and expression in head and neck squamous cell carcinomas. Laryngoscope 104: 1337–1347

    CAS  PubMed  Google Scholar 

  55. Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T, Hirohashi S (1995) Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci USA 92: 7416–7419

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David Hardisson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hardisson, D. Molecular pathogenesis of head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 260, 502–508 (2003). https://doi.org/10.1007/s00405-003-0581-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00405-003-0581-3

Keywords

Navigation