骨髓增生异常综合征/肿瘤（MDS）是一种克隆性血液疾病，其特征是骨髓细胞形态异常和外周血细胞减少。虽然遗传异常是这些疾病及其异质性的发病机制的基础，但目前 MDS 的分类主要依赖于形态学。我们对 3,233 名 MDS 或相关疾病患者进行了基因组分析，以描绘分子亚型并确定其临床意义。基因突变、拷贝数改变 (CNA) 和拷贝中性杂合性丢失 (cnLOH) 来自 152 个基因组的靶向测序，分别在 91%、43% 和 11% 的患者中发现异常。我们利用来自 21 个基因、6 个细胞遗传学事件以及 TP53 和 TET2 位点处的 LOH 的信息，对 16 个分子组进行了表征，涵盖 86% 的患者。由阴性结果定义的两个剩余组（分子上未另有说明，不存在复发驱动因素）占患者的 14%。这些组的患者人数从 0.5% 到 14% 不等，并且与不同的临床表型和结果相关。各组的中位骨髓原始细胞百分比为 1.5% 至 10%，中位总生存期为 0.9 至 8.2 年。我们验证了 5 个特征明确的实体，添加了进一步的证据来支持 3 个先前报告的子集，并描述了 8 个新组。骨髓原始细胞的预后影响取决于遗传亚型。在遗传亚组中，治疗相关的 MDS 和骨髓增生异常/骨髓增殖性肿瘤 (MDS/MPN) 的临床和结果特征与原发性 MDS 相当。总之，MDS 的遗传亚组具有临床相关性，并可能为未来的分类方案和转化治疗研究提供信息。版权所有 © 2024 美国血液学会。

Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage across groups ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research.Copyright © 2024 American Society of Hematology.