文章：

多发性骨髓瘤受黏附和受体酪氨酸激酶信号分子的多种异质体细胞突变的影响

Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules

原文发布日期：2013-02-08

DOI: 10.1038/bcj.2012.47

类型: Original Article

开放获取: 是

英文摘要：

Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient.

摘要翻译： 

多发性骨髓瘤（MM）是一种基本无法治愈的浆细胞恶性肿瘤，其临床病程具有异质性且机制尚未明确。为识别MM中潜在的功能性相关体细胞突变，我们对五例原发MM样本、对应种系DNA及六株MM细胞系进行了全外显子测序，并开发了一种整合38例MM患者已发表突变数据的生物信息学策略。我们的分析证实MM中罕见完全相同的单基因复发突变，但突出显示了突变在重要细胞通路中的聚集现象。具体而言，我们发现MM细胞黏附分子中的突变呈现富集特征，这强调了MM细胞与其微环境相互作用的重要性。我们观察到受体酪氨酸激酶（RTKs）及相关信号效应因子（如EGFR、ERBB3、KRAS和MAP2K2）的突变率升高，提示异常RTK信号在MM发生或进展中发挥作用。影响特定信号网络不同节点的突变多样性似乎是单个MM样本的内在特征，而阐明影响生存通路的突变在个体内及个体间的冗余性，将有助于根据MM患者的具体需求更好地定制靶向治疗策略。

原文链接：

Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules