Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients
Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients
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DOI：
10.1182/blood-2013-12-546309
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发表时间：
2014-10-16
期刊：
影响因子：
20.3
通讯作者：
Pan-Hammarstrom, Qiang
中科院分区：
文献类型：
--
作者：
de Miranda, Noel F. C. C.;Georgiou, Konstantinos;Pan-Hammarstrom, Qiang
弥漫性大b细胞淋巴瘤（DLBCLs）的新一代测序研究揭示了遗传畸变的新靶点，但也存在较高的队列间异质性。先前的研究表明，西方和亚洲患者的疾病亚群患病率和细胞遗传学谱存在差异。为了表征中国DLBCL的编码基因组，我们对来自31个肿瘤和各自外周血样本的DNA进行了全外显子组测序。在另外105份肿瘤样本中研究了B2M、CD70、DTX1、LYN、TMSB4X和UBE2A的突变发生率。我们在DLBCL中发现了11个复发突变的新靶点，包括功能相关基因，如LYN和TMSB4X。在中国队列中发现了其他高频突变基因（>= 10%），包括DTX1，它是Notch通路中最常见的突变靶点。我们进一步证明，DTX1的突变损害了其作为Notch负调节因子的功能。本研究中发现的DLBCL中新的和以前未被发现的体细胞突变靶点支持了这些肿瘤中存在其他/替代的致瘤途径。观察到的与先前报告的差异可能是由于DLBCL的遗传异质性、中国人个体的种系遗传组成和/或暴露于不同的病因所致。
Next-generation sequencing studies on diffuse large B-cell lymphomas (DLBCLs) have revealed novel targets of genetic aberrations but also high intercohort heterogeneity. Previous studies have suggested that the prevalence of disease subgroups and cytogenetic profiles differ between Western and Asian patients. To characterize the coding genome of Chinese DLBCL, we performed whole-exome sequencing of DNA derived from 31 tumors and respective peripheral blood samples. The mutation prevalence of B2M, CD70, DTX1, LYN, TMSB4X, and UBE2A was investigated in an additional 105 tumor samples. We discovered 11 novel targets of recurrent mutations in DLBCL that included functionally relevant genes such as LYN and TMSB4X. Additional genes were found mutated at high frequency (>= 10%) in the Chinese cohort including DTX1, which was the most prevalent mutation target in the Notch pathway. We furthermore demonstrated that mutations in DTX1 impair its function as a negative regulator of Notch. Novel and previous unappreciated targets of somatic mutations in DLBCL identified in this study support the existence of additional/alternative tumorigenic pathways in these tumors. The observed differences with previous reports might be explained by the genetic heterogeneity of DLBCL, the germline genetic makeup of Chinese individuals, and/or exposure to distinct etiological agents.