Targeted deep sequencing reveals clonal and subclonal mutational signatures in Adult T-cell leukemia/lymphoma and defines an unfavorable indolent subtype
Targeted deep sequencing reveals clonal and subclonal mutational signatures in Adult T-cell leukemia/lymphoma and defines an unfavorable indolent subtype
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DOI：
10.1038/s41375-020-0900-3
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发表时间：
2020-06-17
期刊：
影响因子：
11.4
通讯作者：
Hermine, Olivier
中科院分区：
文献类型：
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作者：
Marcais, Ambroise;Lhermitte, Ludovic;Hermine, Olivier
成人T细胞白血病/淋巴瘤（ATL）即使在惰性亚型中也预后不良。我们对61名非洲和加勒比海地区的ATL患者进行了靶向深度测序，并对HTLV-1前病毒整合位点进行了定位。这表明突变主要影响TCR/NF-kB（74%），T细胞运输（46%），免疫逃逸（29%）和细胞周期（26%）相关途径，与之前在日本大型队列中报告的基因组格局一致。为了研究疾病进展时突变特征的演变，同时跟踪恶性克隆的病毒整合结构，我们对复发或从惰性亚型进展为侵袭性亚型的患者进行了纵向研究。对复发患者的系列分析确定了几种克隆进化模式。在进展中的患者中，纵向研究揭示了在诊断时以亚克隆水平存在的进展中的NF-kB/NFAT突变（等位基因频率< 5%）。此外，影响TCR/NF-kB通路的突变的惰性亚型的存在，无论是克隆的还是亚克隆的，与显著较短的进展时间和总生存期相关。我们的观察揭示了ATL突变标记在复发和进展期间的克隆动力学。我们的研究定义了一个新的惰性ATLs亚组，其特征在于具有高转化风险的突变特征。
Adult T-cell leukemia/lymphoma (ATL) carries a poor prognosis even in indolent subtypes. We performed targeted deep sequencing combined with mapping of HTLV-1 proviral integration sites of 61 ATL patients of African and Caribbean origin. This revealed mutations mainly affecting TCR/NF-kB (74%), T-cell trafficking (46%), immune escape (29%), and cell cycle (26%) related pathways, consistent with the genomic landscape previously reported in a large Japanese cohort. To examine the evolution of mutational signatures upon disease progression while tracking the viral integration architecture of the malignant clone, we carried out a longitudinal study of patients who either relapsed or progressed from an indolent to an aggressive subtype. Serial analysis of relapsing patients identified several patterns of clonal evolution. In progressing patients, the longitudinal study revealed NF-kB/NFAT mutations at progression that were present at a subclonal level at diagnosis (allelic frequency < 5%). Moreover, the presence in indolent subtypes of mutations affecting the TCR/NF-kB pathway, whether clonal or subclonal, was associated with significantly shorter time to progression and overall survival. Our observations reveal the clonal dynamics of ATL mutational signatures at relapse and during progression. Our study defines a new subgroup of indolent ATLs characterized by a mutational signature at high risk of transformation.