Telomerase gene mutation screening and telomere overhang detection in Chinese patients with acute myeloid leukemia
Telomerase gene mutation screening and telomere overhang detection in Chinese patients with acute myeloid leukemia
复制标题
中国急性髓系白血病患者端粒酶基因突变筛查及端粒突出检测
DOI：
10.3109/10428194.2012.729834
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发表时间：
2013-07-01
影响因子：
2.6
通讯作者：
Zhao, Yongqiang
中科院分区：
文献类型：
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作者：
Yan, Siyi;Han, Bing;Zhao, Yongqiang
摘要端粒酶复合物基因的功能缺失突变导致端粒酶活性降低，临床上可表现为骨髓功能衰竭，易导致急性髓细胞白血病（AML）。端粒酶功能障碍还导致短端粒突出端，这是一个重要的端粒结构组成部分，并可能导致染色体不稳定。我们筛选了端粒酶逆转录酶（TERT）和端粒酶RNA组分（TERC）基因的变异体，并研究了72例年龄在13-77岁的中国AML患者（61例初治，11例继发，不包括M3）骨髓样本的3 '-突出端长度。评估细胞遗传学、疾病严重程度和短期生存率。鉴定出三种TERT突变（n896 G>A、n1079 C>G和n1451 G>C）。突变携带者的突出端短，预后差。我们发现，与正常对照相比，AML中的突出端长度短得多（p < 0.001）。短突出端与高比例的核型异常和不良预后相关（短突出端组为73.8%，正常组为30%，p=0.001）。多变量分析显示，突出端长度、年龄和不利的染色体异常是AML的独立预后标志物（考克斯回归，p=0.001）。这些数据提高了短突出端长度可能预测AML患者预后不良的可能性。这些发现必须在大型前瞻性研究中得到证实。
Abstract Loss-of-function mutations in telomerase complex genes reduce telomerase activity, and can clinically manifest as bone marrow failure disease, which predisposes to acute myeloid leukemia (AML). Telomerase dysfunction also leads to short telomeric overhang, which is a crucial telomeric structural component, and potentially results in chromosome instability. We screened variants in telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) genes, and investigated the 3’-overhang length in bone marrow samples from 72 Chinese patients with AML (61 de novo, 11 secondary, excluding M3), aged 13–77. Cytogenetics, disease severity and short-term survival were evaluated. Three TERT mutations (n896G>A, n1079C>G and n1451G>C) were identified. Mutation carriers had short overhangs and a poor prognosis. We found that overhang lengths were much shorter in AML compared to normal controls (p < 0.001). Short overhangs were related to a high percentage of karyotype abnormalities and poor prognosis (73.8% in short overhang group vs. 30% in normal group, p=0.001). Multivariant analysis showed that overhang length, age and unfavorable chromosome abnormalities served as independent prognostic markers in AML (Cox regression, p=0.001). These data raise the possibility that short overhang length may predict poor prognosis in patients with AML. These findings would have to be confirmed in large, prospective studies.