Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma
Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma
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DOI：
10.1182/blood-2016-07-729954
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发表时间：
2017-01-26
期刊：
影响因子：
20.3
通讯作者：
Fehniger, Todd A.
中科院分区：
文献类型：
--
作者：
Krysiak, Kilannin;Gomez, Felicia;Fehniger, Todd A.
滤泡性淋巴瘤（FL）是最常见的惰性非霍奇金淋巴瘤，但它仍然只有部分特征在基因组水平。为了提高我们对这种无法治愈的临床异质性疾病的遗传基础的理解，对来自24名FL患者的发现队列的肿瘤/正常对进行全外显子组测序。使用这些数据和在其他B细胞恶性肿瘤中鉴定的突变，对来自105名初次治疗个体的113个FL肿瘤样本中的1716个基因进行测序。我们确定了39个基因，突变显着高于背景突变率。CREBBP突变与较低的PFS相关。相比之下，以前未报道的HVCN 1（一种电压门控质子通道编码基因和B细胞受体信号转导调节剂）突变与PFS改善相关。总共有47例（44.8%）患者在相互关联的B细胞受体（BCR）和CXCR 4信号通路中存在突变。组蛋白基因突变比以前报告的更频繁（在43.8%的患者中确定），并且通常同时发生（17.1%的患者）。在组蛋白H2 B家族的一个后修饰残基上发现了一个新的、经常性的热点。本研究扩大了在淋巴瘤发病机制中涉及的几种已知信号通路和复合物（BCR，Notch，SWitch/蔗糖非发酵（SWI/SNF），空泡ATP酶）中描述的突变基因的数量，并确定了新的复发突变（EGR 1/2，POU 2AF 1，BTK，ZNF 608，HVCN 1），这些突变需要在FL生物学，预后和治疗的背景下进行进一步研究。
Follicular lymphoma(FL) is the most common form of indolent non-Hodgkin lymphoma, yet it remains only partially characterized at the genomic level. To improve our understanding of the genetic underpinnings of this incurable and clinically heterogeneous disease, whole-exome sequencing was performedon tumor/normal pairs from a discovery cohort of 24 patients with FL. Using these data and mutations identified in other B-cell malignancies, 1716 genes were sequenced in 113 FL tumor samples from 105 primarily treatment-naive individuals. We identified 39 genes that were mutated significantly above background mutation rates. CREBBP mutations were associated with inferior PFS. In contrast, mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. In total, 47 (44.8%) patients harbor mutations in the interconnected B-cell receptor (BCR) and CXCR4 signaling pathways. Histone gene mutations were more frequent than previously reported (identified in 43.8% of patients) and often co-occurred (17.1% of patients). A novel, recurrent hotspot was identified at a posttranslationally modified residue in the histone H2B family. This study expands the number of mutated genes described in several known signaling pathways and complexes involved in lymphoma pathogenesis (BCR, Notch, SWitch/sucrose nonfermentable (SWI/SNF), vacuolar ATPases) and identified novel recurrent mutations (EGR1/2, POU2AF1, BTK, ZNF608, HVCN1) that require further investigation in the context of FL biology, prognosis, and treatment.