title: 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.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Evgeniya
authors.initials: E
authors.lastname: Denisova
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Heidenreich
authors.affiliation: Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Nagore
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: P Sivaramakrishna
authors.initials: PS
authors.lastname: Rachakonda
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Ismail
authors.initials: I
authors.lastname: Hosen
authors.affiliation: Interfaculty Institute of Cell Biology, Tuebingen University, and IMPRS ("From Molecules to Organisms"), Tuebingen, Germany.
authors.forename: Ivana
authors.initials: I
authors.lastname: Akrap
authors.affiliation: Department of Pathology, Instituto Valenciano de Oncologia, Valencia, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Traves
authors.affiliation: Laboratory of Molecular Biology, Instituto Valenciano de Oncologia, Valencia, Spain.
authors.forename: Zaida
authors.initials: Z
authors.lastname: García-Casado
authors.affiliation: Laboratory of Molecular Biology, Instituto Valenciano de Oncologia, Valencia, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: López-Guerrero
authors.affiliation: Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Requena
authors.affiliation: Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
authors.forename: Onofre
authors.initials: O
authors.lastname: Sanmartin
authors.affiliation: Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Serra-Guillén
authors.affiliation: Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Llombart
authors.affiliation: Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Guillén
authors.affiliation: Departments of Pathology & Dermatology, Hospital Arnau de Vilanova, Valencia, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Ferrando
authors.affiliation: Departments of Pathology & Dermatology, Hospital Arnau de Vilanova, Valencia, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Gimeno
authors.affiliation: Interfaculty Institute of Cell Biology, Tuebingen University, and IMPRS ("From Molecules to Organisms"), Tuebingen, Germany.|German Cancer Consortium (DKTK/DKFZ), Heidelberg, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008545:Melanoma / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D002352:Carrier Proteins; C483037:DPH3 protein, human; D047908:Intracellular Signaling Peptides and Proteins
keywords: DPH3; OXNAD1; noncoding mutations; skin cancers; whole-exome sequencing