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.
Highlights
Emerging reports have identified frequent somatic mutations within regulatory sequences of the human genome [1,2,3,4]
In this report we show that typical ultraviolet (UV) signature mutations in the promoter region of diphthamide biosynthesis 3 (DPH3) and oxidoreductase NAD-binding domain containing 1 (OXNAD1) genes, adjacent and within a preexisting Ets binding site, occur in melanoma but are common in basal cell (BCC) and squamous cell (SCC) carcinomas of skin
In this communication we report frequent somatic mutations within a bidirectional promoter region of DPH3 and OXNAD1 genes in three major types of skin cancers
Summary
Emerging reports have identified frequent somatic mutations within regulatory sequences of the human genome [1,2,3,4]. The only regulatory mutations that are common in many cancers were reported in the core promoter of the telomerase reverse transcriptase (TERT) gene, which increase TERT transcription through creation of binding motifs for E-twenty six/ternary complex (Ets/TCF) transcription factors [1, 2, 5, 6]. The non-coding mutations in the succinate dehydrogenase complex, subunit D, integral membrane protein (SDHD) and diphthamide biosynthesis 3 (DPH3) promoters have been shown to affect Ets binding motifs and occurred in melanoma at frequencies of 4-10 and 13%, respectively [3, 4, 8]. The mutations in the DPH3 promoter putatively abrogate the pre-existing binding motif for Ets transcription factors, whereas the mutations in TERT promoter result in de novo creation of those motifs
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