Patel Bhumika, Hirsch Cassandra, Clemente Michael, Sekeres Mikkael, Makishima Hideki, Maciejewski Jaroslaw P
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
Int J Hematol. 2015 Mar;101(3):213-8. doi: 10.1007/s12185-015-1747-7. Epub 2015 Feb 18.
Whole exome next generation sequencing systematically applied as a discovery tool in myelodysplastic syndromes (MDS) has led to the identification of a large number of novel mutations. Despite hundreds of patients studied, mutational saturation has not been reached and it is expected that new driver mutations will be discovered in this very heterogeneous condition. Serial samples and deep sequencing of the identified alterations has allowed for a dynamic/chronologic analysis of clonal architecture and identification of a subset of ancestral and secondary molecular lesions. Chromosomal gains and losses have been incorporated into the mutational analyses because they can either cooperate with mutations or produce a functional phenocopy. In addition to the search for somatic defects in MDS, similar discovery studies have been also performed to identify germ line mutations/alterations. Clinical analysis showed applicability of multiplexed somatic mutational panels that would complement current pathomorphologic diagnosis, allow for subclassification of nosologic entities, and enhance predictive power of current prognostic algorithms. Overall, comprehensive genomic analysis in MDS has revealed a tremendous heterogeneity of somatic lesions and their combinations further enhanced by the heterogeneity of clonal architecture and chromosomal lesions.
全外显子组二代测序作为一种发现工具系统地应用于骨髓增生异常综合征（MDS），已导致大量新突变的鉴定。尽管研究了数百名患者，但尚未达到突变饱和，预计在这种非常异质性的疾病中会发现新的驱动突变。对已鉴定改变的系列样本和深度测序允许对克隆结构进行动态/时间分析，并鉴定出一部分祖先和继发分子病变。染色体的获得和缺失已纳入突变分析，因为它们可以与突变协同作用或产生功能性拟表型。除了寻找MDS中的体细胞缺陷外，还进行了类似的发现研究以鉴定种系突变/改变。临床分析表明，多重体细胞突变检测板具有适用性，可补充当前的病理形态学诊断，允许对疾病实体进行亚分类，并增强当前预后算法的预测能力。总体而言，MDS的综合基因组分析揭示了体细胞病变的巨大异质性，而克隆结构和染色体病变的异质性进一步增强了这种异质性。
