Ma Meng, Dai Jie, Xu Tianxiao, Yu Sifan, Yu Huan, Tang Huan, Yan Junya, Wu Xiaowen, Yu Jiayi, Chi Zhihong, Si Lu, Cui Chuanliang, Sheng Xinan, Kong Yan, Guo Jun
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.
J Cancer Res Clin Oncol. 2018 Feb;144(2):257-267. doi: 10.1007/s00432-017-2550-z. Epub 2017 Nov 28.
Mucosal 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 regulator TSC1 and evaluated its correlation with the clinicopathological features of mucosal melanoma.
We collected 91 mucosal melanoma samples for detecting TSC1 mutations. All the coding exons of TSC1 were amplified by PCR and subjected to Sanger sequencing. Expression level of TSC1 encoding protein (hamartin) was detected by immunohistochemistry. The activation of mTOR pathway was determined by evaluating the phosphorylation status of S6RP and 4E-BP1.
The overall mutation frequency of TSC1 was found to be 17.6% (16/91 patients). TSC1 mutations were more inclined to occur in advanced mucosal melanoma (stages III and IV). In the 16 patients with TSC1 mutations, 14 different mutations were detected, affecting 11 different exons. TSC1 mutations were correlated with upregulation of S6RP phosphorylation but were unrelated to 4E-BP1 phosphorylation or hamartin expression. Mucosal melanoma patients with TSC1 mutations had a worse outcome than patients without TSC1 mutations (24.0 versus 34.0 months, P = 0.007).
Our findings suggest that TSC1 mutations are frequent in mucosal melanoma. TSC1 mutations can activate the mTOR pathway through phospho-S6RP and might be a poor prognostic predictor of mucosal melanoma. Our data implicate the potential significance of TSC1 mutations for effective and specific drug therapy for mucosal melanoma.
黏膜黑色素瘤是黑色素瘤中一种相对罕见的亚型，目前尚无明确确立的治疗策略。mTOR信号通路的基因作为包括黑色素瘤在内的癌症治疗的关键靶点，已引起广泛关注。在本研究中，我们旨在调查mTOR上游调节因子TSC1的突变状态，并评估其与黏膜黑色素瘤临床病理特征的相关性。
我们收集了91例黏膜黑色素瘤样本以检测TSC1突变。通过PCR扩增TSC1的所有编码外显子，并进行Sanger测序。采用免疫组织化学法检测TSC1编码蛋白（错构瘤蛋白）的表达水平。通过评估S6RP和4E-BP1的磷酸化状态来确定mTOR通路的激活情况。
发现TSC1的总体突变频率为17.6%（16/91例患者）。TSC1突变更倾向于发生在晚期黏膜黑色素瘤（III期和IV期）。在16例有TSC1突变的患者中，检测到14种不同的突变，影响11个不同的外显子。TSC1突变与S6RP磷酸化上调相关，但与4E-BP1磷酸化或错构瘤蛋白表达无关。有TSC1突变的黏膜黑色素瘤患者的预后比无TSC1突变的患者差（24.0个月对34.0个月，P = 0.007）。
我们的研究结果表明，TSC1突变在黏膜黑色素瘤中很常见。TSC1突变可通过磷酸化S6RP激活mTOR通路，可能是黏膜黑色素瘤预后不良的预测指标。我们的数据表明TSC1突变对于黏膜黑色素瘤有效和特异性药物治疗具有潜在意义。
