Mutations in the promoter of telomerase in cancer

Authors and affiliations:
João Vinagre (1,2,*), Ana Almeida (1,2,*), Helena Pópulo (1,*), Rui Batista (1), Joana Lyra (1,3), Vasco Pinto (1,3), Ricardo Coelho (1,2), Ricardo Celestino (1), Hugo Prazeres (1,4), Luís Lima (2,5,6,7), Miguel Melo (8,9), Adriana Gaspar da Rocha (1,3), Ana Preto (1,10), Patrícia Castro (1), Lígia Castro (3,11), Fernando Pardal (12), José Manuel Lopes (1,3,11), Lúcio Lara Santos (5), Rui Manuel Reis (13,14), José Cameselle-Teijeiro (15), Manuel Sobrinho-Simões (1,3,11), Jorge Lima (1,3), Valdemar Máximo (1,3) & Paula Soares (1,3)

1. Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal

2. Institute of Biomedical Sciences of Abel Salazar, University of Porto, 4050-313 Porto, Portugal

3. Medical Faculty, University of Porto, 4200-319 Porto, Portugal

4. Portuguese Institute of Oncology—Coimbra Centre (IPOFG, EPE), 3000-075 Coimbra, Portugal

5. Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-072 Porto, Portugal

6. Núcleo de Investigação em Farmácia, Centro de Investigação em Saúde e Ambiente (CISA), Health School of the Polytechnic Institute of Porto, 4400-330 Vila Nova de Gaia, Portugal

7. Research Department, Portuguese League Against Cancer (Norte), 4200-177 Porto, Portugal

8. Department of Endocrinology, Diabetes and Metabolism, University Hospital of Coimbra, 3000-075 Coimbra, Portugal

9. Unit of Endocrinology, Medical Faculty, University of Coimbra, 3000-548 Coimbra, Portugal

10. Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal

11. Department of Pathology, Hospital S. João, 4200-319 Porto, Portugal

12. Department of Pathology, Hospital de Braga, 4710-243 Braga, Portugal

13. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal

14. Molecular Oncology Research Center, Barretos Cancer Hospital, CEP 14784-400 São Paulo, Brazil

15. Department of Pathology, Clinical University Hospital, SERGAS, Medical Faculty, University of Santiago de Compostela, IDIS, 15706 Santiago de Compostela, Spain.

* These authors contributed equally to this work. Correspondence and requests for materials should be addressed to P.S. (email: [email protected]).

Abstract:
Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.

Journal:
NATURE COMMUNICATIONS | 4:2185 | DOI: 10.1038/ncomms3185

Link:
http://www.nature.com/naturecommunications