PMID- 26416425
OWN - NLM
STAT- MEDLINE
DCOM- 20161025
LR  - 20191210
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 6
IP  - 34
DP  - 2015 Nov 3
TI  - Frequent DPH3 promoter mutations in skin cancers.
PG  - 35922-30
LID - 10.18632/oncotarget.5771 [doi]
AB  - 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.
FAU - Denisova, Evgeniya
AU  - Denisova E
AD  - Division of Molecular Genetic Epidemiology, German Cancer Research Center, 
      Heidelberg, Germany.
FAU - Heidenreich, Barbara
AU  - Heidenreich B
AD  - Division of Molecular Genetic Epidemiology, German Cancer Research Center, 
      Heidelberg, Germany.
FAU - Nagore, Eduardo
AU  - Nagore E
AD  - Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
FAU - Rachakonda, P Sivaramakrishna
AU  - Rachakonda PS
AD  - Division of Molecular Genetic Epidemiology, German Cancer Research Center, 
      Heidelberg, Germany.
FAU - Hosen, Ismail
AU  - Hosen I
AD  - Division of Molecular Genetic Epidemiology, German Cancer Research Center, 
      Heidelberg, Germany.
FAU - Akrap, Ivana
AU  - Akrap I
AD  - Interfaculty Institute of Cell Biology, Tuebingen University, and IMPRS ("From 
      Molecules to Organisms"), Tuebingen, Germany.
FAU - Traves, Victor
AU  - Traves V
AD  - Department of Pathology, Instituto Valenciano de Oncologia, Valencia, Spain.
FAU - Garcia-Casado, Zaida
AU  - Garcia-Casado Z
AD  - Laboratory of Molecular Biology, Instituto Valenciano de Oncologia, Valencia, 
      Spain.
FAU - Lopez-Guerrero, Jose Antonio
AU  - Lopez-Guerrero JA
AD  - Laboratory of Molecular Biology, Instituto Valenciano de Oncologia, Valencia, 
      Spain.
FAU - Requena, Celia
AU  - Requena C
AD  - Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
FAU - Sanmartin, Onofre
AU  - Sanmartin O
AD  - Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
FAU - Serra-Guillen, Carlos
AU  - Serra-Guillen C
AD  - Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
FAU - Llombart, Beatriz
AU  - Llombart B
AD  - Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
FAU - Guillen, Carlos
AU  - Guillen C
AD  - Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
FAU - Ferrando, Jose
AU  - Ferrando J
AD  - Departments of Pathology & Dermatology, Hospital Arnau de Vilanova, Valencia, 
      Spain.
FAU - Gimeno, Enrique
AU  - Gimeno E
AD  - Departments of Pathology & Dermatology, Hospital Arnau de Vilanova, Valencia, 
      Spain.
FAU - Nordheim, Alfred
AU  - Nordheim A
AD  - Interfaculty Institute of Cell Biology, Tuebingen University, and IMPRS ("From 
      Molecules to Organisms"), Tuebingen, Germany.
AD  - German Cancer Consortium (DKTK/DKFZ), Heidelberg, Germany.
FAU - Hemminki, Kari
AU  - Hemminki K
AD  - Division of Molecular Genetic Epidemiology, German Cancer Research Center, 
      Heidelberg, Germany.
AD  - Center for Primary Health Care Research, Lund University, Malmo, Sweden.
FAU - Kumar, Rajiv
AU  - Kumar R
AD  - Division of Molecular Genetic Epidemiology, German Cancer Research Center, 
      Heidelberg, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Carrier Proteins)
RN  - 0 (DPH3 protein, human)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
SB  - IM
MH  - Amino Acid Sequence
MH  - Base Sequence
MH  - Carcinoma, Squamous Cell/*genetics/pathology
MH  - Carrier Proteins/*genetics
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins
MH  - Melanoma/genetics/pathology
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Promoter Regions, Genetic
MH  - Skin Neoplasms/*genetics/pathology
PMC - PMC4742151
OTO - NOTNLM
OT  - DPH3
OT  - OXNAD1
OT  - noncoding mutations
OT  - skin cancers
OT  - whole-exome sequencing
COIS- CONFLICTS OF INTEREST The authors declare no competing financial interests.
EDAT- 2015/09/30 06:00
MHDA- 2016/10/26 06:00
PMCR- 2015/11/03
CRDT- 2015/09/30 06:00
PHST- 2015/08/10 00:00 [received]
PHST- 2015/09/12 00:00 [accepted]
PHST- 2015/09/30 06:00 [entrez]
PHST- 2015/09/30 06:00 [pubmed]
PHST- 2016/10/26 06:00 [medline]
PHST- 2015/11/03 00:00 [pmc-release]
AID - 5771 [pii]
AID - 10.18632/oncotarget.5771 [doi]
PST - ppublish
SO  - Oncotarget. 2015 Nov 3;6(34):35922-30. doi: 10.18632/oncotarget.5771.