Nagore Eduardo, Heidenreich Barbara, Rachakonda Sívaramakrishna, Garcia-Casado Zaida, Requena Celia, Soriano Virtudes, Frank Christoph, Traves Victor, Quecedo Esther, Sanjuan-Gimenez Josefa, Hemminki Kari, Landi Maria Teresa, Kumar Rajiv
Department of Dermatology, Instituto Valenciano De Oncologia, Valencia, Spain.
Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
Int J Cancer. 2016 Jul 1;139(1):75-84. doi: 10.1002/ijc.30042. Epub 2016 Mar 2.
Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.
尽管靶向治疗取得了进展，但晚期黑色素瘤的治疗仍然是一项疾病管理工作，因此需要生物标志物来识别原发性黑色素瘤高危患者。在本研究中，我们旨在评估原发性黑色素瘤中TERT启动子突变的预后价值。对300例I/II期黑色素瘤患者的肿瘤进行TERT启动子及BRAF/NRAS突变测序。以无进展生存期和黑色素瘤特异性生存期为指标，绘制有突变和无突变患者的累积曲线。采用Cox比例风险回归模型确定突变对生存期的影响。单独来看，TERT启动子和BRAF/NRAS突变的存在与无病生存期和黑色素瘤特异性生存期较差相关，且TERT启动子内的rs2853669多态性会改变这种影响。TERT启动子和BRAF/NRAS突变同时出现时，无病生存期的风险比（HR）为2.3（95%CI 1.2 - 4.4），黑色素瘤特异性生存期的HR为5.8（95%CI 1.9 - 18.3）。该多态性变异等位基因非携带者中，突变对黑色素瘤特异性生存期的影响显著（HR 4.5，95%CI 1.4 - 15.2），但由于事件数量少，变异等位基因携带者的影响无法计算。变异等位基因本身与生存期延长相关（HR 0.3，95%CI 0.1 - 0.9）。本研究数据提供了初步证据，表明TERT启动子突变与BRAF/NRAS突变联合可用于识别侵袭性疾病高危患者，并且通过纳入TERT启动子内的rs2853669多态性有可能优化分类。
