文章：

惰性慢性淋巴细胞白血病中复发突变基因的预后特征与克隆模式

Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia

原文发布日期：2015-08-28

DOI: 10.1038/bcj.2015.65

类型: Original Article

开放获取: 是

英文摘要：

An increasing numbers of patients are being diagnosed with asymptomatic early-stage chronic lymphocytic leukemia (CLL), with no treatment indication at baseline. We applied a high-throughput deep-targeted analysis, especially designed for covering widely TP53 and ATM genes, in 180 patients with inactive disease at diagnosis, to test the independent prognostic value of CLL somatic recurrent mutations. We found that 40/180 patients harbored at least one acquired variant with ATM (n=17, 9.4%), NOTCH1 (n=14, 7.7%), TP53 (n=14, 7.7%) and SF3B1 (n=10, 5.5%) as most prevalent mutated genes. Harboring one ‘sub-Sanger’ TP53 mutation granted an independent 3.5-fold increase of probability of needing treatment. Those patients with a double-hit ATM lesion (mutation+11q deletion) had the shorter median time to first treatment (17 months). We found that a genomic variable: TP53 mutations, most of them under the sensitivity of conventional techniques; a cell phenotypic factor: CD38-positive expression; and a classical marker as β2-microglobulin, remained as the unique independent predictors of outcome. The high-throughput determination of TP53 status, particularly in this set of patients frequently lacking high-risk chromosomal aberrations, emerges as a key step, not only for prediction modeling, but also for exploring mutation-specific therapeutic approaches and minimal residual disease monitoring.

摘要翻译： 

被诊断为无症状早期慢性淋巴细胞白血病（CLL）且基线时无治疗指征的患者日益增多。我们采用高通量深度靶向分析技术（专门设计用于广泛覆盖TP53和ATM基因），对180例确诊时疾病呈惰性状态的患者进行检测，以评估CLL体细胞高频突变的独立预后价值。研究发现，40/180例患者携带至少一种获得性变异，其中ATM（17例，9.4%）、NOTCH1（14例，7.7%）、TP53（14例，7.7%）和SF3B1（10例，5.5%）为最常见突变基因。携带"亚桑格"TP53突变可使需要治疗的概率独立增加3.5倍。存在ATM双打击病变（突变+11q缺失）的患者至首次治疗中位时间最短（17个月）。研究确认基因组变量（TP53突变，其中多数突变低于常规技术检测灵敏度）、细胞表型因素（CD38阳性表达）及经典标志物β2-微球蛋白仍是预后的独立预测因子。高通量检测TP53状态——尤其在这类常缺乏高危染色体异常的患者群体中——不仅成为预测模型构建的关键步骤，更为探索突变特异性治疗策略及微小残留病监测提供重要依据。

原文链接：

Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia