Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas.
Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas.
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深度测序揭示了与 B 细胞淋巴瘤复发相关的克隆进化模式和突变事件。
DOI：
10.1186/s13059-014-0432-0
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发表时间：
2014-08-15
期刊：
影响因子：
12.3
通讯作者：
Elemento O
中科院分区：
文献类型：
--
作者：
Jiang Y;Redmond D;Nie K;Eng KW;Clozel T;Martin P;Tan LH;Melnick AM;Tam W;Elemento O
与弥漫性大B细胞淋巴瘤（DLBCL）频繁复发相关的分子机制尚不明确。尤其是原发性肿瘤克隆异质性如何导致复发还不清楚。在此，我们利用B细胞淋巴瘤的独特特征——VDJ重组和体细胞高频突变——来解决这一问题。
我们对14对匹配的诊断 - 复发肿瘤的重排VDJ连接进行了高通量测序，其中7对进一步进行了外显子组测序。我们确定了DLBCL复发的两种独特克隆进化模式：一种是早期分化模式，其中克隆相关的诊断和复发肿瘤早期分化并平行发展；另一种是晚期分化模式，其中复发肿瘤由诊断肿瘤直接发展而来，分化较小。通过在VDJ连接所提供的系统发育信息背景下检查突变模式，我们确定了诸如KMT2D等表观遗传修饰因子的突变是淋巴瘤发生的潜在早期驱动事件，以及免疫逃逸改变是与复发相关的事件。
总之，我们的研究首次提供了重要证据，表明DLBCL复发可能源于多种不同的肿瘤进化机制，为针对每种机制的治疗提供了理论依据。此外，这项研究强调了迫切需要了解表观遗传修饰因子突变在淋巴瘤发生中的驱动作用，以及免疫监视因子基因损伤在复发中的作用。
本文的在线版本（doi:10.1186/s13059 - 014 - 0432 - 0）包含补充材料，授权用户可获取。
Molecular mechanisms associated with frequent relapse of diffuse large B-cell lymphoma (DLBCL) are poorly defined. It is especially unclear how primary tumor clonal heterogeneity contributes to relapse. Here, we explore unique features of B-cell lymphomas - VDJ recombination and somatic hypermutation - to address this question. We performed high-throughput sequencing of rearranged VDJ junctions in 14 pairs of matched diagnosis-relapse tumors, among which 7 pairs were further characterized by exome sequencing. We identify two distinctive modes of clonal evolution of DLBCL relapse: an early-divergent mode in which clonally related diagnosis and relapse tumors diverged early and developed in parallel; and a late-divergent mode in which relapse tumors developed directly from diagnosis tumors with minor divergence. By examining mutation patterns in the context of phylogenetic information provided by VDJ junctions, we identified mutations in epigenetic modifiers such as KMT2D as potential early driving events in lymphomagenesis and immune escape alterations as relapse-associated events. Altogether, our study for the first time provides important evidence that DLBCL relapse may result from multiple, distinct tumor evolutionary mechanisms, providing rationale for therapies for each mechanism. Moreover, this study highlights the urgent need to understand the driving roles of epigenetic modifier mutations in lymphomagenesis, and immune surveillance factor genetic lesions in relapse. The online version of this article (doi:10.1186/s13059-014-0432-0) contains supplementary material, which is available to authorized users.
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影响因子：
64.5
作者：
BEREK, C;BERGER, A;APEL, M
通讯作者：
APEL, M
DOI：
10.1073/pnas.0801523105
发表时间：
2008-09-02
影响因子：
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作者：
Goodarzi H;Elemento O;Tavazoie S
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