Objectives The transcription factor SOX2 (3q26.3-q27) is an embryonic stem cell factor contributing to the induction of pluripotency in terminally differentiated somatic cells. Recently, amplification of the SOX2 gene locus has been described in squamous cell carcinoma (SCC) of different organ sites. Aim of this study was to investigate amplification and expression status of SOX2 in sinonasal carcinomas and to correlate the results with clinico-pathological data. Materials and Methods A total of 119 primary tumor samples from the sinonasal region were assessed by fluorescence in-situ hybridization and immunohistochemistry for SOX2 gene amplification and protein expression, respectively. Of these, 59 were SSCs, 18 sinonasal undifferentiated carcinomas (SNUC), 10 carcinomas associated with an inverted papilloma (INVC), 19 adenocarcinomas (AD) and 13 adenoid cystic carcinomas (ACC). Results SOX2 amplifications were found in subsets of SCCs (37.5%), SNUCs (35.3%), INVCs (37.5%) and ADs (8.3%) but not in ACCs. SOX2 amplification resulted in increased protein expression. Patients with SOX2-amplified sinonasal carcinomas showed a significantly higher rate of tumor recurrences than SOX2 non-amplified tumors. Conclusion This is the first study assessing SOX2 amplification and expression in a large cohort of sinonasal carcinomas. As opposed to AD and ACC, SOX2 amplifications were detected in more than 1/3 of all SCCs, SNUCs and INVCs. We therefore suggest that SNUCs are molecularly closely related to SCCs and INVCs and that these entities represent a subgroup of sinonasal carcinomas relying on SOX2 acquisition during oncogenesis. SOX2 amplification appears to identify sinonasal carcinomas that are more likely to relapse after primary therapy, suggesting that these patients might benefit from a more aggressive therapy regime.
References
[1]
Lango MN, Topham NS, Perlis CS, Flieder DB, Weaver MW, et al. (2010) Surgery in the multimodality treatment of sinonasal malignancies. Curr Probl Cancer 34: 304–321.
[2]
Guntinas-Lichius O, Kreppel MP, Stuetzer H, Semrau R, Eckel HE, et al. (2007) Single modality and multimodality treatment of nasal and paranasal sinuses cancer: a single institution experience of 229 patients. Eur J Surg Oncol 33: 222–228.
[3]
Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T (2001) Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Cancer 92: 3012–3029.
[4]
Khademi B, Moradi A, Hoseini S, Mohammadianpanah M (2009) Malignant neoplasms of the sinonasal tract: report of 71 patients and literature review and analysis. Oral Maxillofac Surg 13: 191–199.
[5]
Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, et al. (2007) Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 9: 625–635.
[6]
Fong H, Hohenstein KA, Donovan PJ (2008) Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells. Stem Cells 26: 1931–1938.
[7]
Adachi K, Suemori H, Yasuda SY, Nakatsuji N, Kawase E (2010) Role of SOX2 in maintaining pluripotency of human embryonic stem cells. Genes Cells 15: 455–470.
[8]
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861–872.
[9]
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, et al. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917–1920.
[10]
Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, et al. (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448: 318–324.
[11]
Lengerke C, Fehm T, Kurth R, Neubauer H, Scheble V, et al. (2011) Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma. BMC Cancer 11: 42.
[12]
Maier S, Wilbertz T, Braun M, Scheble V, Reischl M, et al. (2011) SOX2 amplification is a common event in squamous cell carcinomas of different organ sites. Hum Pathol 42: 1078–1088.
[13]
Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, et al. (2009) SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 41: 1238–1242.
[14]
Hussenet T, Dali S, Exinger J, Monga B, Jost B, et al. (2010) SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas. PLoS One 5: e8960.
[15]
Yuan P, Kadara H, Behrens C, Tang X, Woods D, et al. (2010) Sex determining region Y-Box 2 (SOX2) is a potential cell-lineage gene highly expressed in the pathogenesis of squamous cell carcinomas of the lung. PLoS One 5: e9112.
[16]
Sholl LM, Long KB, Hornick JL (2010) Sox2 expression in pulmonary non-small cell and neuroendocrine carcinomas. Appl Immunohistochem Mol Morphol 18: 55–61.
[17]
Wilbertz T, Wagner P, Petersen K, Stiedl AC, Scheble VJ, et al. (2011) SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer. Mod Pathol 24: 944–953.
[18]
Sholl LM, Barletta JA, Yeap BY, Chirieac LR, Hornick JL (2010) Sox2 protein expression is an independent poor prognostic indicator in stage I lung adenocarcinoma. Am J Surg Pathol 34: 1193–1198.
[19]
Freier K, Knoepfle K, Flechtenmacher C, Pungs S, Devens F, et al. (2010) Recurrent copy number gain of transcription factor SOX2 and corresponding high protein expression in oral squamous cell carcinoma. Genes Chromosomes Cancer 49: 9–16.
Frohling S, Dohner H (2008) Chromosomal abnormalities in cancer. N Engl J Med 359: 722–734.
[23]
Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, et al. (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40: 499–507.
[24]
Jeter CR, Badeaux M, Choy G, Chandra D, Patrawala L, et al. (2009) Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells 27: 993–1005.
[25]
Rosen JM, Jordan CT (2009) The increasing complexity of the cancer stem cell paradigm. Science 324: 1670–1673.
[26]
Lu Y, Futtner C, Rock JR, Xu X, Whitworth W, et al. (2010) Evidence that SOX2 overexpression is oncogenic in the lung. PLoS One 5: e11022.
[27]
Wang Q, He W, Lu C, Wang Z, Wang J, et al. (2009) Oct3/4 and Sox2 are significantly associated with an unfavorable clinical outcome in human esophageal squamous cell carcinoma. Anticancer Res 29: 1233–1241.
[28]
Du L, Yang Y, Xiao X, Wang C, Zhang X, et al. (2011) Sox2 nuclear expression is closely associated with poor prognosis in patients with histologically node-negative oral tongue squamous cell carcinoma. Oral Oncol 47: 709–713.
