Advertisement

Cellular Oncology

, Volume 37, Issue 1, pp 29–39 | Cite as

Genetic gains and losses in oral squamous cell carcinoma: impact on clinical management

  • Ilda Patrícia Ribeiro
  • Francisco Marques
  • Francisco Caramelo
  • João Pereira
  • Miguel Patrício
  • Hugo Prazeres
  • José Ferrão
  • Maria José Julião
  • Miguel Castelo-Branco
  • Joana Barbosa de Melo
  • Isabel Poiares Baptista
  • Isabel Marques CarreiraEmail author
Original Paper

Abstract

Purpose

The identification of genetic markers associated with oral cancer is considered essential to improve the diagnosis, prognosis, early tumor and relapse detection and, ultimately, to delineate individualized therapeutic approaches. Here, we aimed at identifying such markers.

Methods

Multiplex Ligation-dependent Probe Amplification (MLPA) analyses encompassing 133 cancer-related genes were performed on a panel of primary oral tumor samples and its corresponding resection margins (macroscopically tumor-free tissue) allowing, in both types of tissue, the detection of a wide arrange of copy number imbalances on various human chromosomes.

Results

We found that in tumor tissue, from the 133 cancer-related genes included in this study, those that most frequently exhibited copy number gains were located on chromosomal arms 3q, 6p, 8q, 11q, 16p, 16q, 17p, 17q and 19q, whereas those most frequently exhibiting copy number losses were located on chromosomal arms 2q, 3p, 4q, 5q, 8p, 9p, 11q and 18q. Several imbalances were highlighted, i.e., losses of ERBB4, CTNNB1, NFKB1, IL2, IL12B, TUSC3, CDKN2A, CASP1, and gains of MME, BCL6, VEGF, PTK2, PTP4A3, RNF139, CCND1, FGF3, CTTN, MVP, CDH1, BRCA1, CDKN2D, BAX, as well as exon 4 of TP53. Comparisons between tumor and matched macroscopically tumor-free tissues allowed us to build a logistic regression model to predict the tissue type (benign versus malignant). In this model, the TUSC3 gene showed statistical significance, indicating that loss of this gene may serve as a good indicator of malignancy.

Conclusions

Our results point towards relevance of the above mentioned cancer-related genes as putative genetic markers for oral cancer. For practical clinical purposes, these genetic markers should be validated in additional studies.

Keywords

Oral squamous cell carcinoma Genetic profile Chromosomal imbalances Copy number losses and gains 

Notes

Acknowledgments

The authors are grateful to Dr. Artur Ferreira, Director of the Maxillofacial Surgery Unit from Coimbra Hospital and University Centre, for his contribution in the collection of the samples. This work was supported in part by CIMAGO (Center of Investigation on Environment Genetics and Oncobiology - Faculty of Medicine, University of Coimbra).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

13402_2013_161_MOESM1_ESM.doc (84 kb)
Supplementary Table 1 (DOC 84 kb)

References

  1. 1.
    A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, M.J. Thun, Cancer statistics, 2009. CA Cancer J. Clin. 59(4), 225–249 (2009)PubMedCrossRefGoogle Scholar
  2. 2.
    S. Ambatipudi, M. Gerstung, R. Gowda, P. Pai, A.M. Borges, A.A. Schaffer, N. Beerenwinkel, M.B. Mahimkar, Genomic profiling of advanced-stage oral cancers reveals chromosome 11q alterations as markers of poor clinical outcome. PLoS One 6(2), e17250 (2011)PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    L.P. Kowalski, Results of salvage treatment of the neck in patients with oral cancer. Arch. Otolaryngol. Head Neck Surg. 128(1), 58–62 (2002)PubMedCrossRefGoogle Scholar
  4. 4.
    S.A. Liu, Y.K. Wong, J.C. Lin, C.K. Poon, K.C. Tung, W.C. Tsai, Impact of recurrence interval on survival of oral cavity squamous cell carcinoma patients after local relapse. Otolaryngol. Head Neck Surg. 136(1), 112–118 (2007)PubMedCrossRefGoogle Scholar
  5. 5.
    A. Nathanson, K. Ågren, A. Biörklund, M.G. Lind, L. Andréason, M. Anniko, A. Freijd, L. Lejdeborn, S. Kinman, A. Kumlien, A. Köling, J. Lindström, A. Novik, J. Olofsson, K.-L. Pettersson, Evaluation of some prognostic factors in small squamous cell carcinoma of the mobile tongue: a multicenter study in Sweden. Head Neck 11(5), 387–392 (1989)PubMedCrossRefGoogle Scholar
  6. 6.
    W.R. Rate, P. Garrett, R. Hamaker, M. Singer, N. Pugh, D. Ross, R. Haerr, G. Charles, Intraoperative radiation therapy for recurrent head and neck cancer. Cancer 67(11), 2738–2740 (1991)PubMedCrossRefGoogle Scholar
  7. 7.
    W. Wang, S. Han, Z. Yao, X. Li, P. Huang, M. Zhang, Y. Chen, J. He, A study of epidemiologic and recurrence factors of oral cancer. J. Oral Maxillofac. Surg. (2011)Google Scholar
  8. 8.
    L.Y. Wong, W.I. Wei, L.K. Lam, A.P. Yuen, Salvage of recurrent head and neck squamous cell carcinoma after primary curative surgery. Head Neck 25(11), 953–959 (2003)PubMedCrossRefGoogle Scholar
  9. 9.
    B.J. Braakhuis, R.H. Brakenhoff, C.R. Leemans, Second field tumors: a new opportunity for cancer prevention? Oncologist 10(7), 493–500 (2005)PubMedCrossRefGoogle Scholar
  10. 10.
    D. Weiss, C. Stockmann, K. Schrodter, C. Rudack, Protein expression and promoter methylation of the candidate biomarker TCF21 in head and neck squamous cell carcinoma. Cell Oncol (Dordr) 36(3), 213–224 (2013)CrossRefGoogle Scholar
  11. 11.
    M.A. Guervos, C.A. Marcos, M. Hermsen, A.S. Nuno, C. Suarez, J.L. Llorente, Deletions of N33, STK11 and TP53 are involved in the development of lymph node metastasis in larynx and pharynx carcinomas. Cell. Oncol. 29(4), 327–334 (2007)PubMedGoogle Scholar
  12. 12.
    C. Wittekind, F.L. Greene, R.V.P. Hutter, M. Klimpfinger, L.H. Sobin, TNM atlas. Illustrated Guide to the TNM/pTNM Classification of Malignant Tumours, 5th edn. (UICC), I.U.A.C., (Springer-Verlag, Berlin-Heidelberg-New York, 2003)Google Scholar
  13. 13.
    J.P. Schouten, C.J. McElgunn, R. Waaijer, D. Zwijnenburg, F. Diepvens, G. Pals, Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 30(12), e57 (2002)PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    R.J. Nobre, E. Cruz, O. Real, L.P. de Almeida, T.C. Martins, Characterization of common and rare human papillomaviruses in Portuguese women by the polymerase chain reaction, restriction fragment length polymorphism and sequencing. J. Med. Virol. 82(6), 1024–1032 (2010)PubMedCrossRefGoogle Scholar
  15. 15.
    N.L. Barnes, S. Khavari, G.P. Boland, A. Cramer, W.F. Knox, N.J. Bundred, Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast. Clin. Cancer Res. 11(6), 2163–2168 (2005)PubMedCrossRefGoogle Scholar
  16. 16.
    K. Freier, C. Hofele, K. Knoepfle, M. Gross, F. Devens, G. Dyckhoff, P. Plinkert, P. Lichter, C. Herold-Mende, Cytogenetic characterization of head and neck squamous cell carcinoma cell lines as model systems for the functional analyses of tumor-associated genes. J. Oral Pathol. Med. 39(5), 382–389 (2010)PubMedGoogle Scholar
  17. 17.
    B. Singh, S.K. Gogineni, P.G. Sacks, A.R. Shaha, J.P. Shah, A. Stoffel, P.H. Rao, Molecular cytogenetic characterization of head and neck squamous cell carcinoma and refinement of 3q amplification. Cancer Res. 61(11), 4506–4513 (2001)PubMedGoogle Scholar
  18. 18.
    C.A. Marcos, M. Alonso-Guervos, N.R. Prado, T.S. Gimeno, F.D. Iglesias, M. Hermsen, J.L. Llorente, Genetic model of transformation and neoplastic progression in laryngeal epithelium. Head Neck 33(2), 216–224 (2010)CrossRefGoogle Scholar
  19. 19.
    N. Uzawa, D. Akanuma, A. Negishi, H. Iwaki, Y. Uzawa, T. Amagasa, M.A. Yoshida, Homozygous deletions on the short arm of chromosome 3 in human oral squamous cell carcinomas. Oral Oncol. 37(4), 351–356 (2001)PubMedCrossRefGoogle Scholar
  20. 20.
    M.A. Pershouse, A.K. El-Naggar, K. Hurr, H. Lin, W.K. Yung, P.A. Steck, Deletion mapping of chromosome 4 in head and neck squamous cell carcinoma. Oncogene 14(3), 369–373 (1997)PubMedCrossRefGoogle Scholar
  21. 21.
    X.L. Wang, K. Uzawa, F.L. Imai, H. Tanzawa, Localization of a novel tumor suppressor gene associated with human oral cancer on chromosome 4q25. Oncogene 18(3), 823–825 (1999)PubMedCrossRefGoogle Scholar
  22. 22.
    E.J. Mao, S.M. Schwartz, J.R. Daling, A.M. Beckmann, Loss of heterozygosity at 5q21-22 (adenomatous polyposis coli gene region) in oral squamous cell carcinoma is common and correlated with advanced disease. J. Oral Pathol. Med. 27(7), 297–302 (1998)PubMedCrossRefGoogle Scholar
  23. 23.
    R.A. Brekken, J.P. Overholser, V.A. Stastny, J. Waltenberger, J.D. Minna, P.E. Thorpe, Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice. Cancer Res. 60(18), 5117–5124 (2000)PubMedGoogle Scholar
  24. 24.
    L.C. da Silva Veiga, N.A. Bergamo, P.P. dos Reis, L.P. Kowalski, S.R. Rogatto, DNA gains at 8q23.2: a potential early marker in head and neck carcinomas. Cancer Genet. Cytogenet. 146(2), 110–115 (2003)PubMedCrossRefGoogle Scholar
  25. 25.
    S.C. Lin, Y.J. Chen, S.Y. Kao, M.T. Hsu, C.H. Lin, S.C. Yang, T.Y. Liu, K.W. Chang, Chromosomal changes in betel-associated oral squamous cell carcinomas and their relationship to clinical parameters. Oral Oncol. 38(3), 266–273 (2002)PubMedCrossRefGoogle Scholar
  26. 26.
    C. Garnis, B.P. Coe, A. Ishkanian, L. Zhang, M.P. Rosin, W.L. Lam, Novel regions of amplification on 8q distinct from the MYC locus and frequently altered in oral dysplasia and cancer. Gene Chromosome Cancer 39(1), 93–98 (2004)CrossRefGoogle Scholar
  27. 27.
    C. Garnis, B.P. Coe, L. Zhang, M.P. Rosin, W.L. Lam, Overexpression of LRP12, a gene contained within an 8q22 amplicon identified by high-resolution array CGH analysis of oral squamous cell carcinomas. Oncogene 23(14), 2582–2586 (2004)PubMedCrossRefGoogle Scholar
  28. 28.
    J.D. Cha, H.J. Kim, I.H. Cha, Genetic alterations in oral squamous cell carcinoma progression detected by combining array-based comparative genomic hybridization and multiplex ligation-dependent probe amplification. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 111(5), 594–607 (2011)PubMedCrossRefGoogle Scholar
  29. 29.
    S.M. Gollin, Chromosomal alterations in squamous cell carcinomas of the head and neck: window to the biology of disease. Head Neck 23(3), 238–253 (2001)PubMedCrossRefGoogle Scholar
  30. 30.
    A. Sparano, K.M. Quesnelle, M.S. Kumar, Y. Wang, A.J. Sylvester, M. Feldman, D.A. Sewell, G.S. Weinstein, M.S. Brose, Genome-wide profiling of oral squamous cell carcinoma by array-based comparative genomic hybridization. Laryngoscope 116(5), 735–741 (2006)PubMedCrossRefGoogle Scholar
  31. 31.
    S.L. Cooke, J.C. Pole, S.F. Chin, I.O. Ellis, C. Caldas, P.A. Edwards, High-resolution array CGH clarifies events occurring on 8p in carcinogenesis. BMC Cancer 8, 288 (2008)PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    M.J. Worsham, G. Pals, J.P. Schouten, R.M. Van Spaendonk, A. Concus, T.E. Carey, M.S. Benninger, Delineating genetic pathways of disease progression in head and neck squamous cell carcinoma. Arch. Otolaryngol. Head Neck Surg. 129(7), 702–708 (2003)PubMedCrossRefGoogle Scholar
  33. 33.
    J.W. Rocco, D. Sidransky, p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp. Cell Res. 264(1), 42–55 (2001)PubMedCrossRefGoogle Scholar
  34. 34.
    P. van der Riet, H. Nawroz, R.H. Hruban, R. Corio, K. Tokino, W. Koch, D. Sidransky, Frequent loss of chromosome 9p21-22 early in head and neck cancer progression. Cancer Res. 54(5), 1156–1158 (1994)PubMedGoogle Scholar
  35. 35.
    C. Jin, Y. Jin, D. Gisselsson, J. Wennerberg, T.S. Wah, B. Stromback, Y.L. Kwong, F. Mertens, Molecular cytogenetic characterization of the 11q13 amplicon in head and neck squamous cell carcinoma. Cytogenet Genome Res 115(2), 99–106 (2006)PubMedCrossRefGoogle Scholar
  36. 36.
    R.A. Parikh, J.S. White, X. Huang, D.W. Schoppy, B.E. Baysal, R. Baskaran, C.J. Bakkenist, W.S. Saunders, L.C. Hsu, M. Romkes, S.M. Gollin, Loss of distal 11q is associated with DNA repair deficiency and reduced sensitivity to ionizing radiation in head and neck squamous cell carcinoma. Gene Chromosome Cancer 46(8), 761–775 (2007)CrossRefGoogle Scholar
  37. 37.
    K. Freier, C. Sticht, C. Hofele, C. Flechtenmacher, D. Stange, L. Puccio, G. Toedt, B. Radlwimmer, P. Lichter, S. Joos, Recurrent coamplification of cytoskeleton-associated genes EMS1 and SHANK2 with CCND1 in oral squamous cell carcinoma. Gene Chromosome Cancer 45(2), 118–125 (2006)CrossRefGoogle Scholar
  38. 38.
    H. Mineta, K. Miura, S. Takebayashi, Y. Ueda, K. Misawa, H. Harada, J. Wennerberg, M. Dictor, Cyclin D1 overexpression correlates with poor prognosis in patients with tongue squamous cell carcinoma. Oral Oncol. 36(2), 194–198 (2000)PubMedCrossRefGoogle Scholar
  39. 39.
    A. Namazie, S. Alavi, O.I. Olopade, G. Pauletti, N. Aghamohammadi, M. Aghamohammadi, J.A. Gornbein, T.C. Calcaterra, D.J. Slamon, M.B. Wang, E.S. Srivatsan, Cyclin D1 amplification and p16(MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors. Laryngoscope 112(3), 472–481 (2002)PubMedCrossRefGoogle Scholar
  40. 40.
    Z. Yu, P.M. Weinberger, B.G. Haffty, C. Sasaki, C. Zerillo, J. Joe, D. Kowalski, J. Dziura, R.L. Camp, D.L. Rimm, A. Psyrri, Cyclin D1 is a valuable prognostic marker in oropharyngeal squamous cell carcinoma. Clin. Cancer Res. 11(3), 1160–1166 (2005)PubMedGoogle Scholar
  41. 41.
    U. Duvvuri, D.J. Shiwarski, D. Xiao, C. Bertrand, X. Huang, R.S. Edinger, J.R. Rock, B.D. Harfe, B.J. Henson, K. Kunzelmann, R. Schreiber, R.S. Seethala, A.M. Egloff, X. Chen, V.W. Lui, J.R. Grandis, S.M. Gollin, TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression. Cancer Res. 72(13), 3270–3281 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    O. Nilsson, Profiling of ileal carcinoids. Neuroendocrinology 97(1), 7–18 (2013)PubMedCrossRefGoogle Scholar
  43. 43.
    M.H. Mossink, A. van Zon, R.J. Scheper, P. Sonneveld, E.A. Wiemer, Vaults: a ribonucleoprotein particle involved in drug resistance? Oncogene 22(47), 7458–7467 (2003)PubMedCrossRefGoogle Scholar
  44. 44.
    N. Pecina-Slaus, M. Kljaic, T. Nikuseva-Martic, Loss of heterozygosity of APC and CDH1 genes in laryngeal squamous cell carcinoma. Pathol. Res. Pract. 201(8–9), 557–563 (2005)PubMedCrossRefGoogle Scholar
  45. 45.
    D. Hardisson, C. Alvarez-Marcos, A. Salas-Bustamante, M. Alonso-Guervos, N. Sastre, A. Sampedro, Numerical aberrations of chromosomes 8, 9, 11, and 17 in squamous cell carcinoma of the pharynx and larynx: a fluorescence in situ hybridization and DNA flow cytometric analysis of 50 cases. Oral Oncol. 40(4), 409–417 (2004)PubMedCrossRefGoogle Scholar
  46. 46.
    C. Scully, J.K. Field, H. Tanzawa, Genetic aberrations in oral or head and neck squamous cell carcinoma (SCCHN): 1. Carcinogen metabolism, DNA repair and cell cycle control. Oral Oncol. 36(3), 256–263 (2000)PubMedCrossRefGoogle Scholar
  47. 47.
    A. Carneiro, A. Isinger, A. Karlsson, J. Johansson, G. Jonsson, P.O. Bendahl, D. Falkenback, B. Halvarsson, M. Nilbert, Prognostic impact of array-based genomic profiles in esophageal squamous cell cancer. BMC Cancer 8, 98 (2008)PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    C.L. Martin, S.C. Reshmi, T. Ried, W. Gottberg, J.W. Wilson, J.K. Reddy, P. Khanna, J.T. Johnson, E.N. Myers, S.M. Gollin, Chromosomal imbalances in oral squamous cell carcinoma: examination of 31 cell lines and review of the literature. Oral Oncol. 44(4), 369–382 (2008)PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    B.J.M. Braakhuis, E. Bloemena, C.R. Leemans, R.H. Brakenhoff, Molecular analysis of surgical margins in head and neck cancer: more than a marginal issue. Oral Oncol. 46(7), 485–491 (2010)PubMedCrossRefGoogle Scholar
  50. 50.
    J. Califano, P. van der Riet, W. Westra, H. Nawroz, G. Clayman, S. Piantadosi, R. Corio, D. Lee, B. Greenberg, W. Koch, D. Sidransky, Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res. 56(11), 2488–2492 (1996)PubMedGoogle Scholar
  51. 51.
    A. Bahl, P. Kumar, L. Dar, B.K. Mohanti, A. Sharma, A. Thakar, V. Karthikeyan, K. Sikka, C. Singh, K. Poo, J. Lodha, Prevalence and trends of human papillomavirus in oropharyngeal cancer in a predominantly north Indian population. Head Neck, (2013)Google Scholar
  52. 52.
    M.L. Gillison, Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity. Semin. Oncol. 31(6), 744–754 (2004)PubMedCrossRefGoogle Scholar
  53. 53.
    C.R. Leemans, B.J. Braakhuis, R.H. Brakenhoff, The molecular biology of head and neck cancer. Nat. Rev. Cancer 11(1), 9–22 (2011)PubMedCrossRefGoogle Scholar

Copyright information

© International Society for Cellular Oncology 2013

Authors and Affiliations

  • Ilda Patrícia Ribeiro
    • 1
    • 2
  • Francisco Marques
    • 2
    • 3
    • 4
  • Francisco Caramelo
    • 5
  • João Pereira
    • 5
  • Miguel Patrício
    • 5
  • Hugo Prazeres
    • 6
  • José Ferrão
    • 1
  • Maria José Julião
    • 7
  • Miguel Castelo-Branco
    • 5
  • Joana Barbosa de Melo
    • 1
    • 2
  • Isabel Poiares Baptista
    • 2
    • 3
  • Isabel Marques Carreira
    • 1
    • 2
    Email author
  1. 1.Cytogenetics and Genomics Laboratory, Faculty of MedicineUniversity of Coimbra, Polo Ciências da SaúdeCoimbraPortugal
  2. 2.CIMAGO - Center of Investigation on Environment Genetics and Oncobiology - Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  3. 3.Department of Dentistry, Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  4. 4.Stomatology UnitCoimbra Hospital and University Centre, CHUC, EPECoimbraPortugal
  5. 5.Laboratory of Biostatistics and Medical Informatics, IBILI - Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  6. 6.Molecular Pathology LaboratoryPortuguese Institute of Oncology of Coimbra FG, EPECoimbraPortugal
  7. 7.Department of PathologyCoimbra Hospital and University Centre, CHUC, EPECoimbraPortugal

Personalised recommendations