Frequent genetic aberrations in the cell cycle related genes in mucosal melanoma indicate the potential for targeted therapy
Frequent genetic aberrations in the cell cycle related genes in mucosal melanoma indicate the potential for targeted therapy
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粘膜黑色素瘤细胞周期相关基因的频繁遗传畸变表明靶向治疗的潜力
DOI：
10.1186/s12967-019-1987-z
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发表时间：
2019-07-29
影响因子：
7.4
通讯作者：
Kong, Yan
中科院分区：
文献类型：
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作者：
Xu, Longwen;Cheng, Zhiyuan;Kong, Yan
背景黑色素瘤是最具侵袭性的癌症之一，预后极差，IV期患者的中位生存期约为6~8个月。与皮肤黑色素瘤不同，黏膜黑色素瘤是白种人中罕见的黑色素瘤亚型，但在中国患者中的发病率仍高达22.6%。筛选特定的遗传变异是选择靶向药物治疗晚期黑色素瘤的指导原则，而粘膜黑色素瘤的遗传变异谱和潜在的治疗靶点在很大程度上还不清楚。迫切需要寻找黏膜黑色素瘤的潜在基因变异，以便开发有效的靶向治疗方法。方法收集213例中国黏膜黑色素瘤患者的肿瘤标本。采用Quantigene Plex DNA方法检测p16INK4a/Cyclin D1/CDK4拷贝数，分析异常拷贝数与临床病理参数的关系。采用患者来源的异种移植模型(PDX)检测CDK4/6抑制剂对CDK4途径(CDK4、Cyclin D1和P16INK4a)拷贝数改变的黏膜黑色素瘤细胞增殖的影响。结果在213份标本中，CDK4和CCND1的扩增率分别为47.0%和27.7%，P16INK4a的缺失率为57.7%。有一种以上基因异常的患者占81.7%。CDK4途径基因拷贝数变异与黏膜黑色素瘤患者的预后无关(P >； 0.05)。药敏试验表明，广谱CDK抑制剂AT7519和特异性CDK4/6抑制剂PD0332991对CDK4信号通路异常的黏膜黑色素瘤细胞来源的PDX肿瘤生长的抑制作用高于CDK4信号通路正常的细胞。RNA-seq分析显示CDK4抑制剂可能通过多条信号通路影响肿瘤细胞增殖。结论粘膜黑色素瘤中细胞周期相关基因拷贝数异常。CDK4/6抑制剂通过异常的CDK4途径显著抑制PDX肿瘤的生长。CDK4信号变异预测CDK4抑制剂治疗粘膜黑色素瘤的有效性。
BackgroundMelanoma is one of the most aggressive cancers with extremely poor prognosis, and the median survival time for stage IV patients is approximately 6 to 8 months. Unlike cutaneous melanoma, mucosal melanoma is a rare melanoma subtype among Caucasian patients but its incidence remains as high as 22.6% among Chinese patients. Screening specific genetic variations is the guideline to select targeted drugs for the treatment of advanced melanoma, whereas the genetic variation spectrum and potential therapeutic targets for mucosal melanoma are largely unclear. It is urgent to identify promising genetic variants for mucosal melanoma so as to develop effective targeted therapies for this disease.MethodsTumor samples from 213 Chinese mucosal melanoma patients were involved in this study. P16INK4a/Cyclin D1/CDK4 copy number was examined using the QuantiGene Plex DNA assay and the correlation between abnormal copy number and clinicopathological parameters was analyzed. Patient-derived xenograft models (PDX) were performed to detect the effects of CDK4/6 inhibitors on the proliferation of mucosal melanoma cells with altered copy number of CDK4 pathway (CDK4, Cyclin D1andP16INK4a). The molecular mechanisms of CDK4/6 inhibitors on the proliferation of mucosal melanoma were analyzed by RNAseq.ResultsAmong the 213 samples, the amplification rate ofCDK4andCCND1was 47.0% and 27.7%, respectively, and the deletion rate ofP16INK4awas 57.7%. Patients with more than one genetic abnormality were up to 81.7%. CDK4 pathway gene copy number variation was not associated with the prognosis of patients with mucosal melanoma (P > 0.05). Drug sensitivity tests showed that AT7519, a broad-spectrum CDK inhibitor, and PD0332991, a specific CDK4/6 inhibitor, exhibited higher inhibitory effect on CDK4 signaling pathway abnormal mucosal melanoma cells-derived PDX tumors growth than CDK4 signaling pathway normal ones. RNA-seq analysis showed that CDK4 inhibitors may affect tumor proliferation through multiple signaling pathways.ConclusionsAbnormal copy number of cell cycle related genes is frequently found in mucosal melanoma. CDK4/6 inhibitors significantly suppress the PDX tumor growth with abnormal CDK4 pathway. CDK4 signaling variations predict the effectiveness of CDK4 inhibitors in mucosal melanoma.