Hematolog, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
Division of Life Science and Department of Chemical and Biological Engineering, Hong Kong University of Science and Technology, Hong Kong.
Ann Oncol. 2018 Apr 1;29(4):966-972. doi: 10.1093/annonc/mdy021.
Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course. Beside patients requiring immediate treatment, others show an initial indolent phase followed by progression and others do not progress for decades. The latter two subgroups usually display mutated IGHV genes and a favorable FISH profile.
Patients with absence of disease progression for over 10 years (10-34) from diagnosis were defined as ultra-stable CLL (US-CLL). Forty US-CLL underwent extensive characterization including whole exome sequencing (WES), ultra-deep sequencing and copy number aberration (CNA) analysis to define their unexplored genetic landscape. Microarray analysis, comparing US-CLL with non-US-CLL with similar immunogenetic features (mutated IGHV/favorable FISH), was also carried out to recognize US-CLL at diagnosis.
WES was carried out in 20 US-CLL and 84 non-silent somatic mutations in 78 genes were found. When re-tested in a validation cohort of 20 further US-CLL, no recurrent lesion was identified. No clonal mutations of NOTCH1, BIRC3, SF3B1 and TP53 were found, including ATM and other potential progression driving mutations. CNA analysis identified 31 lesions, none with known poor prognostic impact. No novel recurrent lesion was identified: most cases showed no lesions (38%) or an isolated del(13q) (31%). The expression of 6 genes, selected from a gene expression profile analysis by microarray and quantified by droplet digital PCR on a cohort of 79 CLL (58 US-CLL and 21 non-US-CLL), allowed to build a decision-tree capable of recognizing at diagnosis US-CLL patients.
The genetic landscape of US-CLL is characterized by the absence of known unfavorable driver mutations/CNA and of novel recurrent genetic lesions. Among CLL patients with favorable immunogenetics, a decision-tree based on the expression of 6 genes may identify at diagnosis patients who are likely to maintain an indolent disease for decades.
慢性淋巴细胞白血病（CLL）具有异质性的临床病程。除了需要立即治疗的患者外，其他患者表现出初始惰性阶段，随后进展，而其他患者则在数十年内没有进展。后两组患者通常表现为 IGHV 基因发生突变和 FISH 检查结果良好。
从诊断起超过 10 年（10-34 年）没有疾病进展的患者被定义为超稳定 CLL（US-CLL）。40 名 US-CLL 患者接受了广泛的特征描述，包括全外显子组测序（WES）、超深度测序和拷贝数异常（CNA）分析，以确定其未探索的遗传特征。还进行了微阵列分析，将 US-CLL 与具有相似免疫遗传学特征（突变 IGHV/良好 FISH）的非-US-CLL 进行比较，以在诊断时识别 US-CLL。
对 20 名 US-CLL 患者进行了 WES 检测，在 78 个基因中发现了 84 个非沉默性体细胞突变。在对另外 20 名 US-CLL 的验证队列中重新进行检测时，未发现复发性病变。未发现 NOTCH1、BIRC3、SF3B1 和 TP53 的克隆突变，包括 ATM 和其他潜在的进展驱动突变。CNA 分析确定了 31 个病变，没有已知具有不良预后影响的病变。未发现新的复发性病变：大多数病例无病变（38%）或孤立的 del(13q)（31%）。从微阵列基因表达谱分析中选择的 6 个基因的表达，通过对 79 名 CLL 患者（58 名 US-CLL 和 21 名非-US-CLL）的微阵列进行实时定量 PCR 检测，构建了一个决策树，能够在诊断时识别 US-CLL 患者。
US-CLL 的遗传特征是缺乏已知的不良驱动突变/CNA 和新的复发性遗传病变。在具有良好免疫遗传学特征的 CLL 患者中，基于 6 个基因表达的决策树可能在诊断时识别出那些可能数十年内保持惰性疾病的患者。
