Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma
Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma
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DOI：
10.1182/blood-2012-09-457283
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发表时间：
2013-02-28
期刊：
影响因子：
20.3
通讯作者：
Alizadeh, Ash A.
中科院分区：
文献类型：
--
作者：
Green, Michael R.;Gentles, Andrew J.;Alizadeh, Ash A.
滤泡性淋巴瘤（FL）目前是无法治愈的，使用传统的化疗或免疫治疗方案，迫切需要新的策略。高通量测序技术的进步可以揭示致癌途径，这激发了针对可操作体细胞突变的定制治疗的兴趣。然而，为了使突变导向疗法最有效，突变必须均匀地存在于进化的肿瘤细胞以及自我更新的肿瘤细胞前体中。在这里，我们通过亚群的全外显子组测序显示，在大多数基因突变的代表中，FL肿瘤中存在惊人的瘤内克隆多样性。这种多样性捕获了克隆层次结构，以免疫球蛋白体细胞突变和IGH-BCL2易位为参考框架，通过比较诊断和复发肿瘤对，使我们能够区分淋巴瘤发生过程中的早期和晚期遗传事件。我们提供的证据表明，IGH-BCL2易位和CREBBP突变是早期事件，而MLL2和TNFRSF14突变可能代表疾病进化过程中的晚期事件。这些观察结果为哪些遗传病变代表靶向治疗的合适候选人提供了见解。
Follicular lymphoma (FL) is currently incurable using conventional chemotherapy or immunotherapy regimes, compelling new strategies. Advances in high-throughput sequencing technologies that can reveal oncogenic pathways have stimulated interest in tailoring therapies toward actionable somatic mutations. However, for mutation-directed therapies to be most effective, the mutations must be uniformly present in evolved tumor cells as well as in the self-renewing tumor-cell precursors. Here, we show striking intratumoral clonal diversity within FL tumors in the representation of mutations in the majority of genes as revealed by whole exome sequencing of subpopulations. This diversity captures a clonal hierarchy, resolved using immunoglobulin somatic mutations and IGH-BCL2 translocations as a frame of reference and by comparing diagnosis and relapse tumor pairs, allowing us to distinguish early versus late genetic eventsduring lymphomagenesis. We provide evidence that IGH-BCL2 translocations and CREBBP mutations are early events, whereas MLL2 and TNFRSF14 mutations probably represent late events during disease evolution. These observations provide insight into which of the genetic lesions represent suitable candidates for targeted therapies.