Department of Computer Science, University of Toronto, Toronto, ON, Canada.
The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
Leukemia. 2017 Sep;31(9):1928-1935. doi: 10.1038/leu.2017.17. Epub 2017 Jan 16.
The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.
骨髓增生异常综合征向继发性急性髓系白血病（sAML）进展的遗传学机制尚不清楚。在这项研究中，我们使用下一代测序技术对总共 124 名患者的连续样本进行了体细胞突变及其动态分析，其中包括 31 名患者的发现队列和来自两个验证队列的 93 名患者。对发现队列的全外显子组分析表明，31 名患者中的 29 名至少携带与 AML 中八个常见突变途径之一相关的突变。在初始骨髓增生异常诊断时，T 细胞样本中发现了与 DNA 甲基化和剪接机制相关的基因突变，这表明它们作为早期疾病事件的重要性。另一方面，与信号通路相关的体细胞变异在进展过程中出现或其等位基因负担显著增加。我们的结果表明，激活的信号通路中的突变与 sAML 进展之间存在很强的关联。总体而言，我们证明了不同类别的遗传病变在 sAML 的不同阶段以一般固定的顺序发挥作用。
