TERT promoter status and gene copy number gains: effect on TERT expression and association with prognosis in breast cancer.
TERT promoter status and gene copy number gains: effect on TERT expression and association with prognosis in breast cancer.
复制标题
DOI：
10.18632/oncotarget.20560
复制
发表时间：
2017-09-29
期刊：
影响因子：
--
通讯作者：
Tchirkov A
中科院分区：
文献类型：
--
作者：
Gay-Bellile M;Véronèse L;Combes P;Eymard-Pierre E;Kwiatkowski F;Dauplat MM;Cayre A;Privat M;Abrial C;Bignon YJ;Mouret-Reynier MA;Vago P;Penault-Llorca F;Tchirkov A
人类癌症中端粒酶逆转录酶（TERT）基因的上调会导致端粒酶激活，从而有助于肿瘤细胞的生长优势和存活。 TERT 上调的分子机制很复杂，具有肿瘤特异性，并且具有临床相关性。为了研究乳腺癌中的这些机制，我们对两个乳腺癌队列（总共 122 名患者）中的 TERT 启动子进行了测序，评估了 TERT 拷贝数变化，并评估了 MYC 癌基因（一种已知的转录 TERT 调节因子）的表达。没有发现激活的 TERT 启动子突变，表明这种突变机制不太可能参与乳腺癌中 TERT 的上调。在高达 50% 的病例中发现的 T349C 启动子多态性与 TERT 表达不相关，但 T349C 携带者的无病生存期明显较短。 TERT 增加（15-25% 的病例）与 TERT mRNA 表达增加以及患者无病生存和总生存预后较差密切相关。特别侵袭性乳腺癌的特点是 TERT 增加与 MYC 过度表达相关。这些结果证明了基因拷贝数增加对 TERT 表达水平的显着影响，并为乳腺癌中 TERT 和 MYC 上调的临床意义提供了新的见解。
Upregulation of the telomerase reverse transcriptase (TERT) gene in human cancers leads to telomerase activation, which contributes to the growth advantage and survival of tumor cells. Molecular mechanisms of TERT upregulation are complex, tumor-specific and can be clinically relevant. To investigate these mechanisms in breast cancer, we sequenced the TERT promoter, evaluated TERT copy number changes and assessed the expression of the MYC oncogene, a known transcriptional TERT regulator, in two breast cancer cohorts comprising a total of 122 patients. No activating TERT promoter mutations were found, suggesting that this mutational mechanism is not likely to be involved in TERT upregulation in breast cancer. The T349C promoter polymorphism found in up to 50% of cases was not correlated with TERT expression, but T349C carriers had significantly shorter disease-free survival. TERT gains (15-25% of cases) were strongly correlated with increased TERT mRNA expression and worse patient prognosis in terms of disease-free and overall survival. Particularly aggressive breast cancers were characterized by an association of TERT gains with MYC overexpression. These results evidence a significant effect of gene copy number gain on the level of TERT expression and provide a new insight into the clinical significance of TERT and MYC upregulation in breast cancer.