Clinical and biological implications of driver mutations in myelodysplastic syndromes
Clinical and biological implications of driver mutations in myelodysplastic syndromes
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DOI：
10.1182/blood-2013-08-518886
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发表时间：
2013-11-21
期刊：
影响因子：
20.3
通讯作者：
Campbell, Peter J.
中科院分区：
文献类型：
--
作者：
Papaemmanuil, Elli;Gerstung, Moritz;Campbell, Peter J.
骨髓增生异常综合征（MDS）是一种异质性的慢性血液系统恶性肿瘤，其特征是发育不良、造血功能低下和发展为急性髓系白血病的可变风险。MDS基因组测序已经确定了涉及RNA剪接、DNA修饰、染色质调控和细胞信号传导的基因突变。我们对738例MDS或密切相关肿瘤（包括慢性髓单细胞白血病和MDS-骨髓增生性肿瘤）患者的111个基因进行了测序，以探索获得性突变在MDS生物学和临床表型中的作用。78%的患者有一个或更多的致癌突变。我们确定了基因之间成对关联的复杂模式，表明剪接体机制和表观遗传修饰因子的组成部分的上位相互作用。再加上对亚克隆突变的推断，这些数据提出了一种遗传“宿命”假说，即早期驱动突变（通常影响RNA剪接相关基因）决定了具有不同临床表型的疾病进化的未来轨迹。无论是克隆还是亚克隆，驱动突变具有同等的预后意义，并且随着驱动突变数量的增加，无白血病生存期稳步恶化。因此，在大量特征明确的患者队列中分析致癌突变说明了癌症基因组与疾病生物学之间的相互联系，具有相当大的临床应用潜力。
Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of drivermutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.