TERT promoter mutation subtypes and survival in stage I and II melanoma patients
TERT promoter mutation subtypes and survival in stage I and II melanoma patients
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DOI：
10.1002/ijc.31780
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发表时间：
2019-03-01
影响因子：
6.4
通讯作者：
Nagore, Eduardo
中科院分区：
文献类型：
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作者：
Andres-Lencina, Juan J.;Rachakonda, Sivaramakrishna;Nagore, Eduardo
编码端粒酶逆转录酶亚基的基因启动子内的突变在包括黑色素瘤在内的许多癌症中很常见。此前，TERT 启动子突变被证明与原发性黑色素瘤患者预后不良和生存率降低相关。在这项研究中，我们研究了 TERT 突变亚型对 287 名 I/II 期非肢端黑色素瘤患者的无病生存和黑色素瘤特异性生存的影响。我们的结果表明，在多变量模型中，三种 TERT 启动子突变亚型中，-138/-139 CC > TT 串联突变与最差的无病生存和黑色素瘤特异性生存相关。特别是，与 BRAF/NRAS 突变相结合，-138/-139 CC > TT TERT 启动子突变与统计显着性较差的无病生存率和黑色素瘤特异性生存率相关，风险比为 6.04 (95% CI 2.03-17.94，p = 0.001) 和 12.59 (95% CI 2.18-72.70，p = 0.005），分别。与存活数据相反，荧光素酶测定显示，在具有-124 C > T突变的启动子构建体的实验中观察到最高活性，随后是-138/-139 CC > TT和-146 C > T突变，它们显示出相似的活性。根据之前的报告，我们推测串联突变可能比常见的 TERT 启动子突变导致更大的基因组不稳定性，因此与最差的生存率相关。然而，该研究的结果只是初步的，患者数据有限，因此需要谨慎解释。这项研究中的观察结果如果得到证实，可能会对接受 MAP 激酶抑制剂治疗的黑色素瘤患者产生影响。
Mutations within the promoter of gene encoding telomerase reverse transcriptase subunit are frequent in many cancers including melanoma. Previously, the TERT promoter mutations were shown to associate with markers of poor outcome and reduced survival in patients with primary melanoma. In this study, we investigated the impact of the subtypes of TERT mutations on disease-free and melanoma-specific survival in 287 patients with stage I/II nonacral melanoma. Our results showed that of the three TERT promoter mutation subtypes, in multivariate models, the -138/-139 CC > TT tandem mutation associated with worst disease-free and melanoma-specific survival. In particular, in combination with BRAF/NRAS mutations, the -138/-139 CC > TT TERT promoter mutation associated with statistically significant poor disease-free and melanoma-specific survival with hazard ratios of 6.04 (95% CI 2.03-17.94, p = 0.001) and 12.59 (95% CI 2.18-72.70, p = 0.005), respectively. In contrast to the survival data, luciferase assays showed that the highest activity was observed in experiments with a promoter construct with -124 C > T mutation followed by the -138/-139 CC > TT and -146 C > T mutations, which showed similar activity. Based on previous reports, we speculate that the tandem mutation probably leads to greater genomic instability than the common TERT promoter mutations, hence the association with worst survival. However, the results from the study are only preliminary with limited patient data, therefore, require a cautious interpretation. The observations in this study, if confirmed, could have implications for melanoma patients treated with MAP-kinase inhibitors.