Research Papers:
Analysis of SDHD promoter mutations in various types of melanoma
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Abstract
Simone L. Scholz1, Susanne Horn2, Rajmohan Murali6,7, Inga Möller2, Antje Sucker2, Wiebke Sondermann2, Mathias Stiller2,5, Bastian Schilling2, Elisabeth Livingstone2, Lisa Zimmer2, Henning Reis3, Claudia H. Metz1, Michael Zeschnigk4, Annette Paschen2, Klaus-Peter Steuhl1, Dirk Schadendorf2, Henrike Westekemper1, Klaus G. Griewank2
1Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany
2Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany
3Institute of Pathology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany
4Department of Human Genetics, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany
5University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen Germany
6Department of Pathology, Memorial Sloan Kettering Cancer Center, New York NY, USA
7Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York NY, USA
Correspondence to:
Klaus Griewank, e-mail: [email protected]
Keywords: melanoma, SDHD, promoter mutations
Abbreviations: NGS = next generation sequencing; ETS = E26 transformation-specific; SDHD = Succinate dehydrogenase complex subunit D
Received: May 09, 2015 Accepted: July 15, 2015 Published: July 27, 2015
ABSTRACT
Objectives: Recently, recurrent mutations in regulatory DNA regions, such as promoter mutations in the TERT gene were identified in melanoma. Subsequently, Weinhold et al. reported SDHD promoter mutations occurring in 10% of melanomas and being associated with a lower overall survival rate. Our study analyzes the mutation rate and clinico-pathologic associations of SDHD promoter mutations in a large cohort of different melanoma subtypes.
Methods: 451 melanoma samples (incl. 223 non-acral cutaneous, 38 acral, 33 mucosal, 43 occult, 43 conjunctival and 51 uveal melanoma) were analyzed for the presence of SDHD promoter mutations by Sanger-sequencing. Statistical analysis was performed to screen for potential correlations of SDHD promoter mutation status with various clinico-pathologic criteria.
Results: The SDHD promoter was successfully sequenced in 451 tumor samples. ETS binding site changing SDHD promoter mutations were identified in 16 (4%) samples, of which 5 mutations had not been described previously. Additionally, 5 point mutations not located in ETS binding elements were identified. Mutations in UV-exposed tumors were frequently C>T. One germline C>A SDHD promoter mutation was identified. No statistically significant associations between SDHD promoter mutation status and various clinico-pathologic variables or overall patient survival were observed.
Conclusions: Melanomas harbor recurrent SDHD promoter mutations, which occur primarily as C>T alterations in UV-exposed melanomas. In contrast to the initial report and promoter mutations in the TERT gene, our analysis suggests that SDHD promoter mutations are a relatively rare event in melanoma (4% of tumors) of unclear clinical and prognostic relevance.
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