Abstract
Background
TERT promoter mutations were detected at high frequencies in several cancer types including melanoma. Previous reports showed that these recurrent mutations increase TERT gene expression and the use of TERT mutation status as prognostic factor was suggested.
Objectives
Here we screen a panel of 115 melanoma tumor samples from Austrian patients to evaluate the prevalence and distribution of TERT promoter mutations. The association with clinical and tumor characteristics and the effect on overall survival was analyzed.
Methods
Genomic DNA from formalin-fixed paraffin-embedded tumor samples was isolated followed by PCR amplification, Sanger sequencing and statistical analysis.
Results
We identified TERT promoter mutations in 63 of 115 (54.8%) tumor samples. No statistical significant difference in mutation frequency between primary (22/40 [55%]) and metastatic lesions (41/75 [54.7%]) was detected. BRAF-/NRAS-mutated tumors showed a higher frequency of TERT mutations (pT OR 2.24, 95% CI 0.56–9.02, p = 0.3) (met OR 2.74, 95% CI 0.98–7.66, p = 0.05). In primary melanoma, the presence of alterations in TERT was associated with the carrier status of a common single-nucleotide polymorphism rs2853669 (OR 4.55, CI 1.18–17.52, p = 0.03). In this patient cohort, TERT promoter mutations were not associated with clinical characteristics such as the presence of ulceration or Breslow thickness or showed an effect on overall survival.
Conclusion
Alterations in the TERT promoter region are one of the most frequent mutations in melanoma. Based on this analysis and preliminary evidence, prospective studies will be needed to evaluate the reliability of TERT promoter mutations as prognostic factors in melanoma.
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References
Begus-Nahrmann Y et al (2012) Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis. J Clin Investig 122:2283–2288. doi:10.1172/JCI61745
Bernardes de Jesus B, Blasco MA (2013) Telomerase at the intersection of cancer and aging. Trends Genet 29:513–520. doi:10.1016/j.tig.2013.06.007
Bhalla K et al (2011) PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis. Cancer Res 71:6888–6898. doi:10.1158/0008-5472.CAN-11-1011
Chiba K, Johnson JZ, Vogan JM, Wagner T, Boyle JM, Hockemeyer D (2015) Cancer-associated TERT promoter mutations abrogate telomerase silencing. eLife. doi:10.7554/eLife.07918
Griewank KG et al (2014) TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma. J Natl Cancer Inst. doi:10.1093/jnci/dju246
Heidenreich B et al (2014) Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma Nature. Communications. doi:10.1038/ncomms4401
Hodis E et al (2012) A landscape of driver mutations in melanoma. Cell 150:251–263. doi:10.1016/j.cell.2012.06.024
Horn S et al (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339:959–961. doi:10.1126/science.1230062
Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–959. doi:10.1126/science.1229259
Ko E, H-w Seo, Jung ES, B-h Kim, Jung G (2015) The TERT promoter SNP rs2853669 decreases E2F1 transcription factor binding and increases mortality and recurrence risks in liver cancer vol 7. Impact J. doi:10.18632/oncotarget.6331
Krauthammer M et al (2012) Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44:1006–1014. doi:10.1038/ng.2359
Kubic JD, Little EC, Lui JW, Iizuka T, Lang D (2015) PAX3 and ETS1 synergistically activate MET expression in melanoma cells. Oncogene 34:4964–4974. doi:10.1038/onc.2014.420
Low KC, Tergaonkar V (2013) Telomerase: central regulator of all of the hallmarks of cancer. Trends Biochem Sci 38:426–434. doi:10.1016/j.tibs.2013.07.001
Nagore E et al (2016) TERT promoter mutations in melanoma survival. Int J Cancer. doi:10.1002/ijc.30042
Pópulo H et al (2014) TERT Promoter Mutations in Skin Cancer: the Effects of Sun Exposure and X-Irradiation. J Investig Dermatol 134:2251–2257. doi:10.1038/jid.2014.163
Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA A Cancer J Clin 66:7–30. doi:10.3322/caac.21332
Weinhold N, Jacobsen A, Schultz N, Sander C, Lee W (2014) Genome-wide analysis of noncoding regulatory mutations in cancer. Nat Genet 46:1160–1165. doi:10.1038/ng.3101
Acknowledgements
We thank Lorenzo Cerroni and Isabella Fried (Department of General Dermatology, Medical University Graz, Graz, Austria) for supporting this study and Gerlinde Mayer and Ulrike Schmidbauer (Department of General Dermatology, Medical University Graz, Graz, Austria) for excellent technical assistance.
Funding
This study was funded by the FWF graduate school DK MOLIN.
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The authors RO, CR, BH, RK and DS state no conflict of interest. Author SU has received a honorarium from Roche for attending an advisory board. Author JCB has received speaker honorariums from Amgen, MerckSerono and Pfizer, advisory board honorariums from Amgen, MerckSerono, MSD, Novartis and Takeda as well as research funding from Boehringer Ingelheim, BMS and MerckSerono; none of these activities are related to the submitted report.
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The study was approved by the institutional review board of the Medical University of Graz (ethics votum 24-292 ex 11/12). Informed consent: Informed consent was obtained from all individual participants included in the study.
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Ofner, R., Ritter, C., Heidenreich, B. et al. Distribution of TERT promoter mutations in primary and metastatic melanomas in Austrian patients. J Cancer Res Clin Oncol 143, 613–617 (2017). https://doi.org/10.1007/s00432-016-2322-1
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DOI: https://doi.org/10.1007/s00432-016-2322-1