Oncotarget

Research Papers:

Frequent DPH3 promoter mutations in skin cancers

Evgeniya Denisova, Barbara Heidenreich, Eduardo Nagore, P. Sivaramakrishna Rachakonda, Ismail Hosen, Ivana Akrap, Víctor Traves, Zaida García-Casado, José Antonio López-Guerrero, Celia Requena, Onofre Sanmartin, Carlos Serra-Guillén, Beatriz Llombart, Carlos Guillén, Jose Ferrando, Enrique Gimeno, Alfred Nordheim, Kari Hemminki and Rajiv Kumar _

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Oncotarget. 2015; 6:35922-35930. https://doi.org/10.18632/oncotarget.5771

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Abstract

Evgeniya Denisova1, Barbara Heidenreich1, Eduardo Nagore2, P. Sivaramakrishna Rachakonda1, Ismail Hosen1, Ivana Akrap3, Víctor Traves4, Zaida García-Casado5, José Antonio López-Guerrero5, Celia Requena2, Onofre Sanmartin2, Carlos Serra-Guillén2, Beatriz Llombart2, Carlos Guillén2, Jose Ferrando6, Enrique Gimeno6, Alfred Nordheim3,7, Kari Hemminki1,8 and Rajiv Kumar1

1 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany

2 Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain

3 Interfaculty Institute of Cell Biology, Tuebingen University, and IMPRS (“From Molecules to Organisms”), Tuebingen, Germany

4 Department of Pathology, Instituto Valenciano de Oncologia, Valencia, Spain

5 Laboratory of Molecular Biology, Instituto Valenciano de Oncologia, Valencia, Spain

6 Departments of Pathology & Dermatology, Hospital Arnau de Vilanova, Valencia, Spain

7 German Cancer Consortium (DKTK/DKFZ) Heidelberg, Germany

8 Center for Primary Health Care Research, Lund University, Malmö, Sweden

Correspondence to:

Rajiv Kumar, email:

Keywords: DPH3, OXNAD1, whole-exome sequencing, noncoding mutations, skin cancers

Received: August 10, 2015 Accepted: September 12, 2015 Published: September 21, 2015

Abstract

Recent reports suggested frequent occurrence of cancer associated somatic mutations within regulatory elements of the genome. Based on initial exome sequencing of 21 melanomas, we report frequent somatic mutations in skin cancers in a bidirectional promoter of diphthamide biosynthesis 3 (DPH3) and oxidoreductase NAD-binding domain containing 1 (OXNAD1) genes. The UV-signature mutations occurred at sites adjacent and within a binding motif for E-twenty six/ternary complex factors (Ets/TCF), at -8 and -9 bp from DPH3 transcription start site. Follow up screening of 586 different skin lesions showed that the DPH3 promoter mutations were present in melanocytic nevi (2/114; 2%), melanoma (30/304; 10%), basal cell carcinoma of skin (BCC; 57/137; 42%) and squamous cell carcinoma of skin (SCC; 12/31; 39%). Reporter assays carried out in one melanoma cell line for DPH3 and OXNAD1 orientations showed statistically significant increased promoter activity due to -8/-9CC > TT tandem mutations; although, no effect of the mutations on DPH3 and OXNAD1 transcription in tumors was observed. The results from this study show occurrence of frequent somatic non-coding mutations adjacent to a pre-existing binding site for Ets transcription factors within the directional promoter of DPH3 and OXNAD1 genes in three major skin cancers. The detected mutations displayed typical UV signature; however, the functionality of the mutations remains to be determined.


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