TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas.
TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas.
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TERT 启动子突变导致 IDH 突变，从而预测 WHO II 级和 III 级弥漫性胶质瘤对辅助治疗的差异反应。
DOI：
10.18632/oncotarget.4549
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Mao Y
中科院分区：
文献类型：
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作者：
Zhang ZY;Chan AK;Ding XJ;Qin ZY;Hong CS;Chen LC;Zhang X;Zhao FP;Wang Y;Wang Y;Zhou LF;Zhuang Z;Ng HK;Yan H;Yao Y;Mao Y
IDH突变经常发生在WHO II级和III级弥漫性胶质瘤中，与野生型肿瘤相比预后良好。然而，WHO II级和II级弥漫性胶质瘤中的IDH突变是否预示着对辅助放疗（RT）或化疗（CHT）的敏感性增强仍存在争议。最近的研究发现了胶质瘤中端粒酶逆转录酶（TERT）启动子区的复发性突变。我们以前证明，当与IDH突变结合时，TERT启动子突变可能是胶质瘤生存预测中有希望的生物标志物。本研究分析了295例接受或不接受辅助治疗的WHO II级和III级弥漫性胶质瘤的IDH和TERT启动子突变，以探讨其对肿瘤对遗传毒性治疗敏感性的影响。216例（73.2%）患者发现IDH突变，112例（38%）患者发现TERT启动子突变。在多变量分析中，IDH突变（p < 0.001）是接受遗传毒性治疗患者PFS和OS的独立预后因素，而TERT启动子突变不是。在单变量分析中，IDH和TERT启动子突变在未接受遗传毒性治疗的患者中不是显著的预后因素。在IDH突变的WHO II级和III级弥漫性胶质瘤中，辅助RT和CHT是独立影响PFS的因素（RT p = 0.001，CHT p = 0.026），但在IDH野生型组中则不然。单变量和多变量分析表明，TERT启动子突变进一步分层IDH野生型WHO II级和III级弥漫性胶质瘤分为两个亚组，对遗传毒性治疗的反应不同。佐剂RT和CHT是影响IDH wt/TERTmut亚组中PFS的显著参数（RT p = 0.015，CHT p = 0.015），但在IDH wt/TERTwt亚组中不是。我们的数据表明，IDH突变的WHO II级和III级弥漫性神经胶质瘤的PFS和OS比IDH野生型患者更好，当基因毒性治疗后手术。重要的是，我们还发现，TERT启动子突变进一步将IDH野生型WHO II级和III级弥漫性胶质瘤分为两个亚组，对辅助治疗有不同的反应。总之，TERT启动子突变可能预示IDH野生型WHO II级和III级弥漫性胶质瘤对遗传毒性治疗的敏感性增强，并可能证明该亚组的强化治疗是合理的。
IDH mutations frequently occur in WHO grade II and III diffuse gliomas and have favorable prognosis compared to wild-type tumors. However, whether IDH mutations in WHO grade II and II diffuse gliomas predict enhanced sensitivity to adjuvant radiation (RT) or chemotherapy (CHT) is still being debated. Recent studies have identified recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) in gliomas. We previously demonstrated that TERT promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations. This study analyzed IDH and TERT promoter mutations in 295 WHO grade II and III diffuse gliomas treated with or without adjuvant therapies to explore their impact on the sensitivity of tumors to genotoxic therapies. IDH mutations were found in 216 (73.2%) patients and TERT promoter mutations were found in 112 (38%) patients. In multivariate analysis, IDH mutations (p < 0.001) were independent prognostic factors for PFS and OS in patients receiving genotoxic therapies while TERT promoter mutations were not. In univariate analysis, IDH and TERT promoter mutations were not significant prognostic factors in patients who did not receive genotoxic therapies. Adjuvant RT and CHT were factors independently impacting PFS (RT p = 0.001, CHT p = 0.026) in IDH mutated WHO grade II and III diffuse gliomas but not in IDH wild-type group. Univariate and multivariate analyses demonstrated TERT promoter mutations further stratified IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to genotoxic therapies. Adjuvant RT and CHT were significant parameters influencing PFS in the IDH wt/TERT mut subgroup (RT p = 0.015, CHT p = 0.015) but not in the IDH wt/TERT wt subgroup. Our data demonstrated that IDH mutated WHO grade II and III diffuse gliomas had better PFS and OS than their IDH wild-type counterparts when genotoxic therapies were administered after surgery. Importantly, we also found that TERT promoter mutations further stratify IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to adjuvant therapies. Taken together, TERT promoter mutations may predict enhanced sensitivity to genotoxic therapies in IDH wild-type WHO grade II and III diffuse gliomas and may justify intensified treatment in this subgroup.