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TERT promoter hot spot mutations are frequent in Indian cervical and oral squamous cell carcinomas

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Tumor Biology

Abstract

Squamous cell carcinoma (SCC) of the uterine cervix and oral cavity are most common cancers in India. Telomerase reverse transcriptase (TERT) overexpression is one of the hallmarks for cancer, and activation through promoter mutation C228T and C250T has been reported in variety of tumors and often shown to be associated with aggressive tumors. In the present study, we analyzed these two hot spot mutations in 181 primary tumors of the uterine cervix and oral cavity by direct DNA sequencing and correlated with patient’s clinicopathological characteristics. We found relatively high frequency of TERT hot spot mutations in both cervical [21.4 % (30/140)] and oral [31.7 % (13/41)] squamous cell carcinomas. In cervical cancer, TERT promoter mutations were more prevalent (25 %) in human papilloma virus (HPV)-negative cases compared to HPV-positive cases (20.6 %), and both TERT promoter mutation and HPV infection were more commonly observed in advanced stage tumors (77 %). Similarly, the poor and moderately differentiated tumors of the uterine cervix had both the TERT hot spot mutations and HPV (16 and 18) at higher frequency (95.7 %). Interestingly, we observed eight homozygous mutations (six 228TT and two 250TT) only in cervical tumors, and all of them were found to be positive for high-risk HPV. To the best of our knowledge, this is the first study from India reporting high prevalence of TERT promoter mutations in primary tumors of the uterine cervix and oral cavity. Our results suggest that TERT reactivation through promoter mutation either alone or in association with the HPV oncogenes (E6 and E7) could play an important role in the carcinogenesis of cervical and oral cancers.

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References

  1. Ferlay JSI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC cancer base no. 11. Lyon: International Agency for Research on Cancer; 2012.

    Google Scholar 

  2. Ferlay J SI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC cancer base no. 11. International Agency for Research on Cancer 1.0. 2013.

  3. Bosch FX, de Sanjose S Chapter 1: human papillomavirus and cervical cancer—burden and assessment of causality. J Natl Cancer Inst Monogr. 2003;3–13.

  4. Dikshit R, Gupta PC, Ramasundarahettige C, Gajalakshmi V, Aleksandrowicz L, et al. Cancer mortality in India: a nationally representative survey. Lancet. 2012;379:1807–16.

    Article  PubMed  Google Scholar 

  5. Byakodi R, Byakodi S, Hiremath S, Byakodi J, Adaki S, et al. Oral cancer in India: an epidemiologic and clinical review. J Community Health. 2012;37:316–9.

    Article  PubMed  Google Scholar 

  6. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Betel-quid and areca-nut chewing and some areca-nut-derived nitrosamines. IARC monographs on the evaluation of carcinogenic risks to humans (2003). v. 85.

  7. Gupta PC, Ray CS, Sinha DN, Singh PK. Smokeless tobacco: a major public health problem in the SEA region: a review. Indian J Public Health. 2011;55:199–209.

    Article  PubMed  Google Scholar 

  8. Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW. Telomerase activity in human germline and embryonic tissues and cells. Dev Genet. 1996;18:173–9.

    Article  CAS  PubMed  Google Scholar 

  9. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011–5.

    Article  CAS  PubMed  Google Scholar 

  10. Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer. 1997;33:787–91.

    Article  CAS  PubMed  Google Scholar 

  11. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, et al. TERT promoter mutations in familial and sporadic melanoma. Science. 2013;339:959–61.

    Article  CAS  PubMed  Google Scholar 

  12. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, et al. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339:957–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang Z, Yang X, Meng L, Liu F, Shen C, et al. Enhanced amplification of GC-rich DNA with two organic reagents. Biotechniques. 2009;47:775–9.

    Article  CAS  PubMed  Google Scholar 

  14. Vogelstein B, Kinzler KW. The path to cancer—three strikes and you’re out. N Engl J Med. 2015;373:1895–8.

    Article  PubMed  Google Scholar 

  15. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  16. Cong YS, Wen J, Bacchetti S. The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum Mol Genet. 1999;8:137–42.

    Article  CAS  PubMed  Google Scholar 

  17. Liu X, Bishop J, Shan Y, Pai S, Liu D, et al. Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer. 2013;20:603–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rachakonda PS, Hosen I, de Verdier PJ, Fallah M, Heidenreich B, 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;110:17426–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, 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;110:6021–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Griewank KG, Murali R, Schilling B, Schimming T, Moller I, et al. TERT promoter mutations are frequent in cutaneous basal cell carcinoma and squamous cell carcinoma. PLoS One. 2013;8:e80354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Landa I, Ganly I, Chan TA, Mitsutake N, Matsuse M, et al. Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J Clin Endocrinol Metab. 2013;98:E1562–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu X, Wu G, Shan Y, Hartmann C, von Deimling A, et al. Highly prevalent TERT promoter mutations in bladder cancer and glioblastoma. Cell Cycle. 2013;12:1637–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013;4:2218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vinagre J, Almeida A, Populo H, Batista R, Lyra J, et al. Frequency of TERT promoter mutations in human cancers. Nat Commun. 2013;4:2185.

    Article  CAS  PubMed  Google Scholar 

  25. Cheng KA, Kurtis B, Babayeva S, Zhuge J, Tantchou I, et al. Heterogeneity of TERT promoter mutations status in squamous cell carcinomas of different anatomical sites. Ann Diagn Pathol. 2015;19:146–8.

    Article  PubMed  Google Scholar 

  26. Wu RC, Ayhan A, Maeda D, Kim KR, Clarke BA, et al. Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy. J Pathol. 2014;232:473–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Scott GA, Laughlin TS, Rothberg PG. Mutations of the TERT promoter are common in basal cell carcinoma and squamous cell carcinoma. Mod Pathol. 2014;27:516–23.

    Article  CAS  PubMed  Google Scholar 

  28. Mitra AB, Murty VV, Singh V, Li RG, Pratap M, et al. Genetic alterations at 5p15: a potential marker for progression of precancerous lesions of the uterine cervix. J Natl Cancer Inst. 1995;87:742–5.

    Article  CAS  PubMed  Google Scholar 

  29. Mitra AB, Murty VV, Li RG, Pratap M, et al. Allelotype analysis of cervical carcinoma. Cancer Res. 1994;54:4481–7.

    CAS  PubMed  Google Scholar 

  30. Atkin NB. Significance of chromosome 5 and 17 changes in the development of carcinoma of the cervix uteri. Cytogenet Cell Genet. 2000;91:44–6.

    Article  CAS  PubMed  Google Scholar 

  31. Gewin L, Myers H, Kiyono T, Galloway DA. Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex. Genes Dev. 2004;18:2269–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, et al. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature. 1998;396:84–8.

    Article  CAS  PubMed  Google Scholar 

  33. Liu X, Dakic A, Chen R, Disbrow GL, Zhang Y, et al. Cell-restricted immortalization by human papillomavirus correlates with telomerase activation and engagement of the hTERT promoter by Myc. J Virol. 2008;82:11568–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu X, Disbrow GL, Yuan H, Tomaic V, Schlegel R. Myc and human papillomavirus type 16 E7 genes cooperate to immortalize human keratinocytes. J Virol. 2007;81:12689–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu X, Roberts J, Dakic A, Zhang Y, Schlegel R. HPV E7 contributes to the telomerase activity of immortalized and tumorigenic cells and augments E6-induced hTERT promoter function. Virology. 2008;375:611–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu X, Yuan H, Fu B, Disbrow GL, Apolinario T, et al. The E6AP ubiquitin ligase is required for transactivation of the hTERT promoter by the human papillomavirus E6 oncoprotein. J Biol Chem. 2005;280:10807–16.

    Article  CAS  PubMed  Google Scholar 

  37. Van Doorslaer K, Burk RD. Association between hTERT activation by HPV E6 proteins and oncogenic risk. Virology. 2012;433:216–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Oh ST, Kyo S, Laimins LA. Telomerase activation by human papillomavirus type 16 E6 protein: induction of human telomerase reverse transcriptase expression through Myc and GC-rich Sp1 binding sites. J Virol. 2001;75:5559–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Howie HL, Katzenellenbogen RA, Galloway DA. Papillomavirus E6 proteins. Virology. 2009;384:324–34.

    Article  CAS  PubMed  Google Scholar 

  40. Tungteakkhun SS, Duerksen-Hughes PJ. Cellular binding partners of the human papillomavirus E6 protein. Arch Virol. 2008;153:397–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Dr. Sindhuja, Mrs. Arivazhagi (Arignar Anna Memorial Cancer Hospital & Research Institute, Kanchipuram), and Dr. V. Rajalakshmi (Institute of Obstetrics & Gynaecology and Government General Hospital for Women and Children, Chennai) for clinical assessment and sample collection. We, VV, KA, MM, AKD, and GA gratefully acknowledge the Government of India’s Council of Scientific and Industrial Research (CSIR) and University Grant Commission (UGC), respectively, for providing research fellowships. We also thank DST-FIST and UGC-SAP infrastructure facilities.

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    Authors and Affiliations

    1. Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, 600113, India

      Vilvanathan Vinothkumar, Ganesan Arunkumar, Sundaramoorthy Revathidevi, Kanagaraj Arun, Mayakannan Manikandan, Arunagiri Kuha Deva Magendhra Rao & Arasambattu Kannan Munirajan

    2. Centre for Oncology, Government Royapettah Hospital & Kilpauk Medical College, Chennai, 600014, India

      Kottayasamy Seenivasagam Rajkumar, Chandrasekar Ajay & Ramamurthy Rajaraman

    3. Institute of Social Obstetrics and Government Kasturba Gandhi Hospital for Women and Children, Chennai, 600005, India

      Rajendren Ramani

    4. Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia

      Avaniyapuram Kannan Murugan

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    1. Vilvanathan Vinothkumar
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    Correspondence to Arasambattu Kannan Munirajan.

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    Ethics approval

    The Institutional Ethics Committee, Government Arignar Anna Memorial Cancer Hospital, Kancheepuram (No.101041/e1/2009-2), and the Madras Medical College, Chennai (No.04092010), approved the present study. Cervical and oral cancer samples were collected following the Institutional Ethical Committee (IEC) guidelines and informed consent was obtained from each patient, after explaining about the research study. For the illiterate patients, the study was verbally explained and consent was obtained with their thumb impression.

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    Vilvanathan Vinothkumar and Ganesan Arunkumar contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary Table S1

    Complete clinico-pathological profile of cervical cancer patients with HPV infection and TERT hot spot mutation status. (XLSX 15 kb)

    Supplementary Table S2

    Complete clinico-pathological profile of oral cancer patients with HPV infection and TERT hot spot mutation status. (XLSX 11 kb)

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    Vinothkumar, V., Arunkumar, G., Revathidevi, S. et al. TERT promoter hot spot mutations are frequent in Indian cervical and oral squamous cell carcinomas. Tumor Biol. 37, 7907–7913 (2016). https://doi.org/10.1007/s13277-015-4694-2

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