Frequent DPH3 promoter mutations in skin cancers.

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.

• Authors: 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, Rajiv Kumar
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 34 Pg. 35922-30 (Nov 03 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26416425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• DPH3 protein, human
• Intracellular Signaling Peptides and Proteins

Topics

• Amino Acid Sequence
• Base Sequence
• Carcinoma, Squamous Cell (genetics, pathology)
• Carrier Proteins (genetics)
• Humans
• Intracellular Signaling Peptides and Proteins
• Melanoma (genetics, pathology)
• Molecular Sequence Data
• Mutation
• Promoter Regions, Genetic
• Skin Neoplasms (genetics, pathology)