Hotspot TERT promoter mutations are rare events in testicular germ cell tumors
- 178 Downloads
The abnormal activation of telomerase, codified by the telomerase reverse transcriptase (TERT) gene, is related to one of cancer hallmarks. Hotspot somatic mutations in the promoter region of TERT, specifically the c.-124:C>T and c.-146:C>T, were recently identified in a range of human cancers and have been associated with a more aggressive behavior. Testicular germ cell tumors frequently exhibit a good prognosis; however, the development of refractory disease is still a clinical challenge. In this study, we aim to evaluate for the first time the presence of the hotspot telomerase reverse transcriptase gene promoter mutations in testicular germ cell tumors. A series of 150 testicular germ cell tumor cases and four germ cell tumor cell lines were evaluated by PCR followed by direct Sanger sequencing and correlated with patient’s clinical pathological features. Additionally, we genotyped the telomerase reverse transcriptase gene promoter single nucleotide polymorphism rs2853669 (T>C) located at −245 position. We observed the presence of the TERT promoter mutation in four patients, one exhibited the c.-124:C>T and three the c.-146:C>T. No association between TERT mutation status and clinicopathological features could be identified. The analysis of the rs2853669 showed that variant C was present in 22.8 % of the cases. In conclusion, we showed for the first time that TERT promoter mutations occur in a small subset (~3 %) of testicular germ cell tumors.
KeywordsTesticular neoplasms Neoplasms, germ cell, and embryonal TERT protein Mutation Polymorphism, single nucleotide
The authors acknowledge the support of the Center for Research Support (NAP), Barretos Cancer Hospital, Pio XII Foundation.
Compliance with ethical standards
This work was supported by the Barretos Cancer Hospital internal research funds (PAIP): Project “Microenvironment, metabolism and cancer” that was partially supported by Programa Operacional Regional do Norte (ON.2 – O Novo Norte), under the Quadro de Referência Estratégico Nacional (QREN), and through the Fundo Europeu de Desenvolvimento Regional (FEDER). R.M.R. has a National Counsel of Technological and Scientific Development (CNPq) scholarship.
Conflicts of interest
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (register number CAAE 12297713.0.0000.5437) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.
- 4.Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz Jr LA, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A. 2013;110(15):6021–6. doi: 10.1073/pnas.1303607110.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Rachakonda PS, Hosen I, de Verdier PJ, Fallah M, Heidenreich B, Ryk C, et al. TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism. Proc Natl Acad Sci U S A. 2013;110(43):17426–31. doi: 10.1073/pnas.1310522110.CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Lorch A, Beyer J, Bascoul-Mollevi C, Kramar A, Einhorn LH, Necchi A, et al. Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol: Off J Am Soc Clin Oncol. 2010;28(33):4906–11. doi: 10.1200/JCO.2009.26.8128.CrossRefGoogle Scholar
- 13.Mead GM, Cullen MH, Huddart R, Harper P, Rustin GJ, Cook PA, et al. A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin) given as second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial. Br J Cancer. 2005;93(2):178–84. doi: 10.1038/sj.bjc.6602682.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Martinho O, Longatto-Filho A, Lambros MB, Martins A, Pinheiro C, Silva A, et al. Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas. Br J Cancer. 2009;101(6):973–82. doi: 10.1038/sj.bjc.6605225.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.IGCCCG. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. Int Germ Cell Cancer Collab Group J Clin Oncol: Off J Am Soc Clin Oncol. 1997;15(2):594–603.Google Scholar
- 21.Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013;4:2218. doi: 10.1038/ncomms3218.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Ries LAG YJ, Keel GE, Eisner MP, Lin YD, Horner M-J (editors). SEER survival monograph: cancer survival among adults: U.S. SEER Program, 1988–2001, Patient and Tumor Characteristics. National Cancer Institute, SEER Program, NIH Pub. No. 07–6215, Bethesda, MD, 2007; p165-70. 2007.Google Scholar
- 34.Lopes LF, Macedo CR, Pontes EM, Dos Santos AS, Mastellaro MJ, Melaragno R, et al. Cisplatin and etoposide in childhood germ cell tumor: Brazilian pediatric oncology society protocol GCT-91. J Clin Oncol: Off J Am Soc Clin Oncol. 2009;27(8):1297–303. doi: 10.1200/JCO.2008.16.4202.CrossRefGoogle Scholar