Squamous Cell Carcinoma

  • Timothy Craig Allen
Part of the Molecular Pathology Library book series (MPLB, volume 6)


There are a variety of molecular alterations that are associated with squamous cell carcinoma (SCC), including altered expression and gain of function of oncogenes, loss of tumor suppressor gene function, and epigenetic alterations, such as tumor-acquired aberrant promoter methylation. SCC often has a variety of chromosome gains and losses. Epithelial growth factor receptor (EGFR) is often overexpressed in non-small cell lung cancers and preneoplastic airway lesions. EGFR tyrosine kinase inhibitors (TKIs) have revolutionized first-line pulmonary adenocarcinoma therapy for patients with an EGFR mutation; however, little progress has been made in treatment of SCC, which are usually nonresponsive to EGFR TKI and may be associated with fatal complications if treated with anti-vascular epithelial growth factor therapies. Loss of heterozygosity, the loss of a single parent’s contribution to part of the cell’s genome, frequently indicates in cancers the presence of a tumor suppressor gene in the lost region, for which the remaining copy of the tumor suppressor gene has been inactivated, often by a point mutation. Loss of heterozygosity on chromosome 3p, an important early molecular event in lung carcinogenesis, is found in more than 90% of SCCs. There are distinct regions, thought to contain multiple tumor suppressor genes that are frequently lost. p53 gene dysfunction is the most common and important genetic alteration in lung cancer development, with p53 gene inactivation by mutations or loss of heterozygosity at 17p13 resulting in loss of p53 tumor suppressor functions, thus promoting tumor cell proliferation. p53 loss occurs in the majority of non-small cell lung cancers, and more commonly in SCC than in adenocarcinomas. p53 gene mutations are associated with cigarette smoking, and inactivating p53 gene mutations have been found very early in the carcinogenesis of SCC. Because p53 gene mutations arise in squamous preneoplastic lesions, it is thought that most p53 gene mutations occur before SCC invasion. Telomerase is expressed in most human cancers, including lung cancers. Germ cells and cancer cells maintain telomere length using the enzyme telomerase and are able to divide indefinitely; and the loss of telomere function is thought to accelerate carcinogenesis. Increased telomerase activity in lung cancer and bronchial epithelial dysplasia has been found.


Epidermal Growth Factor Receptor Squamous Cell Carcinoma Epidermal Growth Factor Receptor Telomeric Repeat Amplification Protocol Squamous Cell Carcinoma Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Takeshita M, Koga T, Takayama K, et al. CHFR expression is preferentially impaired in smoking-related squamous cell carcinoma of the lung, and the diminished expression significantly harms outcomes. Int J Cancer. 2008;123:1623–30.PubMedCrossRefGoogle Scholar
  2. 2.
    Lo KC, Stein LC, Panzarella JA, Cowell JK, Hawthorn L. Identification of genes involved in squamous cell carcinoma of the lung using synchronized data from DNA copy number and transcript expression profiling analysis. Lung Cancer. 2008;59:315–31.PubMedCrossRefGoogle Scholar
  3. 3.
    Wistuba II, Behrens C, Virmani AK, et al. Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer. Cancer Res. 1999;59:1973–9.PubMedGoogle Scholar
  4. 4.
    Green MR. TBP-associated factors (TAFIIs): multiple, selective transcriptional mediators in common complexes. Trends Biochem Sci. 2000;25:59–63.PubMedCrossRefGoogle Scholar
  5. 5.
    Sy SM, Wong N, Lee TW, et al. Distinct patterns of genetic alterations in adenocarcinoma and squamous cell carcinoma of the lung. Eur J Cancer. 2004;40:1082–94.PubMedCrossRefGoogle Scholar
  6. 6.
    Wistuba II, Behrens C, Milchgrub S, et al. Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma. Oncogene. 1999;18:643–50.PubMedCrossRefGoogle Scholar
  7. 7.
    Ray M, Salgia R, Vokes EE. The role of EGFR inhibition in the treatment of non-small cell lung cancer. Oncologist. 2009;14:1116–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Bunn Jr PA, Franklin W. Epidermal growth factor receptor expression, signal pathway, and inhibitors in non-small cell lung cancer. Semin Oncol. 2002;29: 38–44.PubMedCrossRefGoogle Scholar
  9. 9.
    Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366:1527–37.PubMedCrossRefGoogle Scholar
  10. 10.
    Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1. J Clin Oncol. 2004;22:777–84.PubMedCrossRefGoogle Scholar
  11. 11.
    Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005;23:5892–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135:622–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.PubMedCrossRefGoogle Scholar
  14. 14.
    Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.PubMedCrossRefGoogle Scholar
  15. 15.
    Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.PubMedCrossRefGoogle Scholar
  17. 17.
    Pirker R, Herth FJ, Kerr KM, et al. Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop. J Thorac Oncol. 2010;5:1706–13.PubMedCrossRefGoogle Scholar
  18. 18.
    Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184–91.PubMedCrossRefGoogle Scholar
  19. 19.
    Hung J, Kishimoto Y, Sugio K, et al. Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma. JAMA. 1995;273:558–63.PubMedCrossRefGoogle Scholar
  20. 20.
    Wistuba II, Gazdar AF. Characteristic genetic alterations in lung cancer. Methods Mol Med. 2003;74: 3–28.PubMedGoogle Scholar
  21. 21.
    Kishimoto Y, Sugio K, Hung JY, et al. Allele-specific loss in chromosome 9p loci in preneoplastic lesions accompanying non-small-cell lung cancers. J Natl Cancer Inst. 1995;87:1224–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Thiberville L, Payne P, Vielkinds J, et al. Evidence of cumulative gene losses with progression of premalignant epithelial lesions to carcinoma of the bronchus. Cancer Res. 1995;55:5133–9.PubMedGoogle Scholar
  23. 23.
    Chung GT, Sundaresan V, Hasleton P, Rudd R, Taylor R, Rabbitts PH. Clonal evolution of lung tumors. Cancer Res. 1996;56:1609–14.PubMedGoogle Scholar
  24. 24.
    Tsuji N, Furuse K, Asanuma K, et al. Mutations of the p53 gene and loss of heterozygosity at chromosome 17p13.1 are associated with increased survivin expression in breast cancer. Breast Cancer Res Treat. 2004;87:23–31.PubMedCrossRefGoogle Scholar
  25. 25.
    Vincenzi B, Schiavon G, Silletta M, et al. Cell cycle alterations and lung cancer. Histol Histopathol. 2006;21:423–35.PubMedGoogle Scholar
  26. 26.
    Mogi A, Kuwano H. TP53 mutations in nonsmall cell lung cancer. J Biomed Biotechnol. 2011;2011:583929.PubMedCrossRefGoogle Scholar
  27. 27.
    Franklin WA, Gazdar AF, Haney J, et al. Widely ­dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis. J Clin Invest. 1997;100:2133–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Chang MY, Chong IW, Chen FM, et al. High frequency of frameshift mutation on p53 gene in Taiwanese with non small cell lung cancer. Cancer Lett. 2005;222:195–204.PubMedCrossRefGoogle Scholar
  29. 29.
    Harris CC. p53 tumor suppressor gene: from the basic research laboratory to the clinic—an abridged historical perspective. Carcinogenesis. 1996;17:1187–98.PubMedCrossRefGoogle Scholar
  30. 30.
    Bennett WP, Colby TV, Travis WD, et al. p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res. 1993;53:4817–22.PubMedGoogle Scholar
  31. 31.
    Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene. 2002;21:7435–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Hecht SS. Progress and challenges in selected areas of tobacco carcinogenesis. Chem Res Toxicol. 2008;21: 160–71.PubMedCrossRefGoogle Scholar
  33. 33.
    Fernandez-Garcia I, Ortiz-de-Solorzano C, Montuenga LM. Telomeres and telomerase in lung cancer. J Thorac Oncol. 2008;3:1085–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Chen CH, Chen RJ. Prevalence of telomerase activity in human cancer. J Formos Med Assoc. 2011;110: 275–89.PubMedCrossRefGoogle Scholar
  35. 35.
    de Lange T. Activation of telomerase in a human tumor. Proc Natl Acad Sci U S A. 1994;91:2882–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Harley CB, Villeponteau B. Telomeres and telomerase in aging and cancer. Curr Opin Genet Dev. 1995;5:249–55.PubMedCrossRefGoogle Scholar
  37. 37.
    Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature. 1998;396: 84–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Chin L, Artandi SE, Shen Q, et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999;97:527–38.PubMedCrossRefGoogle Scholar
  39. 39.
    Artandi SE, DePinho RA. A critical role for telomeres in suppressing and facilitating carcinogenesis. Curr Opin Genet Dev. 2000;10:39–46.PubMedCrossRefGoogle Scholar
  40. 40.
    Wu X, Zhao H, Suk R, Christiani DC. Genetic susceptibility to tobacco-related cancer. Oncogene. 2004;23: 6500–23.PubMedCrossRefGoogle Scholar
  41. 41.
    Hiyama K, Hiyama E, Ishioka S, et al. Telomerase activity in small-cell and non-small-cell lung cancers. J Natl Cancer Inst. 1995;87:895–902.PubMedCrossRefGoogle Scholar
  42. 42.
    Albanell J, Lonardo F, Rusch V, et al. High telomerase activity in primary lung cancers: association with increased cell proliferation rates and advanced pathologic stage. J Natl Cancer Inst. 1997;89:1609–15.PubMedCrossRefGoogle Scholar
  43. 43.
    Yashima K, Litzky LA, Kaiser L, et al. Telomerase expression in respiratory epithelium during the multistage pathogenesis of lung carcinomas. Cancer Res. 1997;57:2373–7.PubMedGoogle Scholar
  44. 44.
    Lantuejoul S, Soria JC, Morat L, et al. Telomere shortening and telomerase reverse transcriptase expression in preinvasive bronchial lesions. Clin Cancer Res. 2005;11:2074–82.PubMedCrossRefGoogle Scholar
  45. 45.
    Miyazu YM, Miyazawa T, Hiyama K, et al. Telomerase expression in noncancerous bronchial epithelia is a possible marker of early development of lung cancer. Cancer Res. 2005;65:9623–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Gottschling S, Jauch A, Kuner R, et al. Establishment and comparative characterization of novel squamous cell non-small cell lung cancer cell lines and their corresponding tumor tissue. Lung Cancer. 2011;75(1):45–57.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of PathologyThe University of Texas Health Science Center at TylerTylerUSA

Personalised recommendations