Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia
Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia
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DOI：
10.1182/blood-2013-11-539726
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发表时间：
2014-04-03
期刊：
影响因子：
20.3
通讯作者：
Gaidano, Gianluca
中科院分区：
文献类型：
--
作者：
Rossi, Davide;Khiabanian, Hossein;Gaidano, Gianluca
TP 53突变是慢性淋巴细胞白血病（CLL）生存率差和难治性的强预测因子，并对疾病管理有直接影响。关于TP 53突变的临床信息限于>20%白血病细胞中代表的病变。在这里，我们测试了非常小的TP 53突变亚克隆的临床影响和化学不耐受性的预测。TP 53基因在309例新诊断的CLL中进行了超深度下一代测序（NGS）。建立了一种稳健的生物信息学算法，用于高度灵敏地检测少数TP 53突变细胞（低至1000个野生型细胞中的3个）。通过独立方法验证次要亚克隆。超深NGS在28/309（9%）未治疗的CLL中鉴定了小的TP 53突变亚克隆，由于其非常低的丰度（中值等位基因频率：2.1%），其被桑格测序遗漏。携带小TP 53突变亚克隆的患者表现出与携带克隆性TP 53病变的患者相同的临床表型和较差的生存率（风险比= 2.01; P = 0.0250）。通过纵向分析，治疗前鉴定的小TP 53突变亚克隆在CLL复发时成为主要群体，并预测了化学难治性的发展。这项研究提供了一个原理证明，即在诊断时检测到的非常小的白血病亚克隆是随后疾病进程的重要驱动因素。
TP53 mutations are strong predictors of poor survival and refractoriness in chronic lymphocytic leukemia (CLL) and have direct implications for disease management. Clinical information on TP53 mutations is limited to lesions represented in >20% leukemic cells. Here, we tested the clinical impact and prediction of chemorefractoriness of very small TP53 mutated subclones. The TP53 gene underwent ultra-deep-next generation sequencing (NGS) in 309 newly diagnosed CLL. A robust bioinformatic algorithm was established for the highly sensitive detection of few TP53 mutated cells (down to 3 out of similar to 1000 wild-type cells). Minor subclones were validated by independent approaches. Ultra-deep-NGS identified small TP53 mutated subclones in 28/309 (9%) untreated CLL that, due to their very low abundance (median allele frequency: 2.1%), were missed by Sanger sequencing. Patients harboring small TP53 mutated subclones showed the same clinical phenotype and poor survival (hazard ratio = 2.01; P = .0250) as those of patients carrying clonal TP53 lesions. By longitudinal analysis, small TP53 mutated subclones identified before treatment became the predominant population at the time of CLL relapse and anticipated the development of chemorefractoriness. This study provides a proof-of-principle that very minor leukemia subclones detected at diagnosis are an important driver of the subsequent disease course.