Analysis of TSC1 mutation spectrum in mucosal melanoma
Analysis of TSC1 mutation spectrum in mucosal melanoma
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DOI：
10.1007/s00432-017-2550-z
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发表时间：
2018-02
影响因子：
3.6
通讯作者：
Meng Ma;J. Dai;Tianxiao Xu;Sifan Yu;Huan Yu;Huan Tang;Junya Yan;Xiaowen Wu;Jiayi Yu;Z. Chi;L. Si;C. Cui;X. Sheng;Y. Kong;Jun Guo
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文献类型：
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作者：
Meng Ma;J. Dai;Tianxiao Xu;Sifan Yu;Huan Yu;Huan Tang;Junya Yan;Xiaowen Wu;Jiayi Yu;Z. Chi;L. Si;C. Cui;X. Sheng;Y. Kong;Jun Guo
粘液性黑色素瘤是一种相对罕见的黑色素瘤亚型，目前尚无明确的治疗策略。mTOR信号通路的基因作为癌症治疗（包括黑色素瘤）的关键靶标引起了极大的关注。在这项研究中，我们的目的是调查上游mTOR regulatorTSC 1的突变状态，并评估其与粘膜melanoma.MethodsWe的临床病理特征的相关性收集91例粘膜黑色素瘤标本检测TSC 1突变。PCR扩增TSC 1基因的所有编码外显子，并进行桑格测序。免疫组化检测TSC 1编码蛋白（hamartin）的表达水平。结果91例恶性黑色素瘤患者中16例（17.6%）发现TSC 1基因突变，其中16例发生在晚期（III、IV期），16例发生在晚期（III、IV期）。在16例TSC 1突变患者中，检测到14种不同的突变，影响11个不同的外显子，TSC 1突变与S6 RP磷酸化上调相关，但与4 E-BP 1磷酸化或Hamartin表达无关。TSC 1突变的粘液黑色素瘤患者的预后比无TSC 1突变的患者差（24.0 vs 34.0个月，P= 0.007）。结论我们的研究结果表明，TSC 1突变在粘液黑色素瘤中很常见，TSC 1突变可以通过磷酸化S6 RP激活mTOR通路，可能是粘液黑色素瘤预后不良的预测因子。我们的数据暗示了TSC 1突变对于粘膜黑色素瘤有效和特异性药物治疗的潜在意义。
PurposeMucosal melanoma is a relatively rare subtype of melanoma for which no clearly established therapeutic strategy exists. The genes of the mTOR signalling pathway have drawn great attention as key targets for cancer treatment, including melanoma. In this study, we aimed to investigate the mutation status of the upstream mTOR regulatorTSC1and evaluated its correlation with the clinicopathological features of mucosal melanoma.MethodsWe collected 91 mucosal melanoma samples for detectingTSC1mutations. All the coding exons ofTSC1were amplified by PCR and subjected to Sanger sequencing. Expression level ofTSC1encoding protein (hamartin) was detected by immunohistochemistry. The activation of mTOR pathway was determined by evaluating the phosphorylation status of S6RP and 4E-BP1.ResultsThe overall mutation frequency ofTSC1was found to be 17.6% (16/91 patients).TSC1mutations were more inclined to occur in advanced mucosal melanoma (stages III and IV). In the 16 patients withTSC1mutations, 14 different mutations were detected, affecting 11 different exons.TSC1mutations were correlated with upregulation of S6RP phosphorylation but were unrelated to 4E-BP1 phosphorylation or hamartin expression. Mucosal melanoma patients withTSC1mutations had a worse outcome than patients withoutTSC1mutations (24.0 versus 34.0 months,P= 0.007).ConclusionsOur findings suggest thatTSC1mutations are frequent in mucosal melanoma.TSC1mutations can activate the mTOR pathway through phospho-S6RP and might be a poor prognostic predictor of mucosal melanoma. Our data implicate the potential significance ofTSC1mutations for effective and specific drug therapy for mucosal melanoma.