Analysis of SDHD promoter mutations in various types of melanoma.
OBJECTIVE
Recently, recurrent mutations in regulatory DNA regions, such as promoter mutations in the TERT gene were identified in melanoma. Subsequently, Weinhold et al. reported SDHD promoter mutations occurring in 10% of melanomas and being associated with a lower overall survival rate. Our study analyzes the mutation rate and clinico-pathologic associations of SDHD promoter mutations in a large cohort of different melanoma subtypes.


METHODS
451 melanoma samples (incl. 223 non-acral cutaneous, 38 acral, 33 mucosal, 43 occult, 43 conjunctival and 51 uveal melanoma) were analyzed for the presence of SDHD promoter mutations by Sanger-sequencing. Statistical analysis was performed to screen for potential correlations of SDHD promoter mutation status with various clinico-pathologic criteria.


RESULTS
The SDHD promoter was successfully sequenced in 451 tumor samples. ETS binding site changing SDHD promoter mutations were identified in 16 (4%) samples, of which 5 mutations had not been described previously. Additionally, 5 point mutations not located in ETS binding elements were identified. Mutations in UV-exposed tumors were frequently C>T. One germline C>A SDHD promoter mutation was identified. No statistically significant associations between SDHD promoter mutation status and various clinico-pathologic variables or overall patient survival were observed.


CONCLUSIONS
Melanomas harbor recurrent SDHD promoter mutations, which occur primarily as C>T alterations in UV-exposed melanomas. In contrast to the initial report and promoter mutations in the TERT gene, our analysis suggests that SDHD promoter mutations are a relatively rare event in melanoma (4% of tumors) of unclear clinical and prognostic relevance.
Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Simone L
SL
Scholz
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Susanne
S
Horn
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York NY, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York NY, USA.
Rajmohan
R
Murali
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Inga
I
Möller
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Antje
A
Sucker
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Wiebke
W
Sondermann
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.|University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen Germany.
Mathias
M
Stiller
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Bastian
B
Schilling
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Elisabeth
E
Livingstone
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Lisa
L
Zimmer
Institute of Pathology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Henning
H
Reis
Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Claudia H
CH
Metz
Department of Human Genetics, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Michael
M
Zeschnigk
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Annette
A
Paschen
Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Klaus-Peter
KP
Steuhl
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Dirk
D
Schadendorf
Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Henrike
H
Westekemper
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Klaus G
KG
Griewank
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D003230:Conjunctival Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D004252:DNA Mutational Analysis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D013385:Succinate Dehydrogenase / Q000235:genetics*; D013472:Sunlight / Q000009:adverse effects; D013997:Time Factors; D014466:Ultraviolet Rays / Q000009:adverse effects; D014604:Uveal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D055815:Young Adult; D000098943:Uveal Melanoma
D014408:Biomarkers, Tumor; D050783:Proto-Oncogene Proteins c-ets; C491545:SDHD protein, human; D013385:Succinate Dehydrogenase
SDHD; melanoma; promoter mutations