Mutational Intratumor Heterogeneity is a Complex and Early Event in the Development of Adult T-cell Leukemia/Lymphoma.
Mutational Intratumor Heterogeneity is a Complex and Early Event in the Development of Adult T-cell Leukemia/Lymphoma.
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DOI：
10.1016/j.neo.2018.07.001
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Watanabe T
中科院分区：
文献类型：
--
作者：
Farmanbar A;Firouzi S;Makałowski W;Kneller R;Iwanaga M;Utsunomiya A;Nakai K;Watanabe T
肿瘤的克隆结构在其发病机制和侵袭性中起着至关重要的作用;然而，目前尚不清楚这种克隆性如何促成不同的恶性肿瘤。在这项研究中，我们试图解决突变瘤内异质性（ITH）在成人T细胞白血病/淋巴瘤（ATL）。ATL是一种恶性肿瘤，其分子发病机制尚不完全清楚，由人T细胞白血病病毒1型（HTLV-1）感染引起。为了通过肿瘤遗传多样性谱确定克隆结构，我们研究了来自71名ATL患者的142个肿瘤和匹配的正常样本的全外显子组测序数据。基于SciClone分析，ATL样品在克隆/亚克隆频率范围内显示出从1到9个簇的宽谱模式。聚类的平均数是6个样本，但不同的样本之间的聚类数不同。在这些ATL样本中，94%有两个以上的集群。侵袭性ATL病例的克隆簇略多于惰性类型，表明在疾病的早期阶段存在ITH。ATL中已知的显著突变基因经常聚集在一起，并可能共存于同一克隆中。IRF 4、CCR 4、TP 53和PLCG 1突变几乎聚集在具有中等变异等位基因频率（VAF）的亚克隆中，而HLA-B、CARD 11和NOTCH 1突变聚集在具有较低VAF的亚克隆中。综上所述，这些结果表明ATL显示出高度的ITH和复杂的亚克隆结构。我们的研究结果表明，克隆/亚克隆结构可能是一个有用的措施，预后的目的和个性化的评估治疗反应。
The clonal architecture of tumors plays a vital role in their pathogenesis and invasiveness; however, it is not yet clear how this clonality contributes to different malignancies. In this study we sought to address mutational intratumor heterogeneity (ITH) in adult T-cell leukemia/lymphoma (ATL). ATL is a malignancy with an incompletely understood molecular pathogenesis caused by infection with human T-cell leukemia virus type-1 (HTLV-1). To determine the clonal structure through tumor genetic diversity profiles, we investigated 142 whole-exome sequencing data of tumor and matched normal samples from 71 ATL patients. Based on SciClone analysis, the ATL samples showed a wide spectrum of modes over clonal/subclonal frequencies ranging from one to nine clusters. The average number of clusters was six across samples, but the number of clusters differed among different samples. Of these ATL samples, 94% had more than two clusters. Aggressive ATL cases had slightly more clonal clusters than indolent types, indicating the presence of ITH during earlier stages of disease. The known significantly mutated genes in ATL were frequently clustered together and possibly coexisted in the same clone. IRF4, CCR4, TP53, and PLCG1 mutations were almost clustered in subclones with a moderate variant allele frequency (VAF), whereas HLA-B, CARD11, and NOTCH1 mutations were clustered in subclones with lower VAFs. Taken together, these results show that ATL displays a high degree of ITH and a complex subclonal structure. Our findings suggest that clonal/subclonal architecture might be a useful measure for prognostic purposes and personalized assessment of the therapeutic response.
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影响因子：
12.3
作者：
Firouzi S;López Y;Suzuki Y;Nakai K;Sugano S;Yamochi T;Watanabe T
通讯作者：
Watanabe T
影响因子：
6.2
作者：
Kawano, Noriaki;Shimoda, Kazuya;Harada, Mine
通讯作者：
Harada, Mine
影响因子：
82.9
作者：
Andor N;Graham TA;Jansen M;Xia LC;Aktipis CA;Petritsch C;Ji HP;Maley CC
通讯作者：
Maley CC
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
28.2
作者：
Greaves M
通讯作者：
Greaves M