Scholz Simone L, Horn Susanne, Murali Rajmohan, Möller Inga, Sucker Antje, Sondermann Wiebke, Stiller Mathias, Schilling Bastian, Livingstone Elisabeth, Zimmer Lisa, Reis Henning, Metz Claudia H, Zeschnigk Michael, Paschen Annette, Steuhl Klaus-Peter, Schadendorf Dirk, Westekemper Henrike, Griewank Klaus G
Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), Essen Germany.
Oncotarget. 2015 Sep 22;6(28):25868-82. doi: 10.18632/oncotarget.4665.
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.
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.
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.
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.
最近，在黑色素瘤中发现了调控DNA区域的复发性突变，如TERT基因中的启动子突变。随后，温霍尔德等人报告称，10%的黑色素瘤中存在SDHD启动子突变，且与较低的总生存率相关。我们的研究分析了一大群不同黑色素瘤亚型中SDHD启动子突变的发生率及其临床病理相关性。
通过桑格测序分析451例黑色素瘤样本（包括223例非肢端皮肤黑色素瘤、38例肢端黑色素瘤、33例黏膜黑色素瘤、43例隐匿性黑色素瘤、43例结膜黑色素瘤和51例葡萄膜黑色素瘤）中SDHD启动子突变的存在情况。进行统计分析以筛选SDHD启动子突变状态与各种临床病理标准之间的潜在相关性。
451个肿瘤样本成功对SDHD启动子进行了测序。在16个（4%）样本中鉴定出改变ETS结合位点的SDHD启动子突变，其中5个突变此前未被描述。此外，还鉴定出5个不在ETS结合元件中的点突变。紫外线暴露肿瘤中的突变多为C>T。鉴定出1个种系C>A SDHD启动子突变。未观察到SDHD启动子突变状态与各种临床病理变量或患者总生存率之间存在统计学显著相关性。
黑色素瘤存在复发性SDHD启动子突变，主要表现为紫外线暴露黑色素瘤中的C>T改变。与最初的报告及TERT基因启动子突变不同，我们的分析表明，SDHD启动子突变在黑色素瘤中相对少见（占肿瘤的4%），其临床和预后相关性尚不清楚。
