Genome-Wide Somatic Alterations in Multiple Myeloma Reveal a Superior Outcome Group
Genome-Wide Somatic Alterations in Multiple Myeloma Reveal a Superior Outcome Group
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DOI：
10.1200/jco.20.00461
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发表时间：
2020-09-20
影响因子：
45.3
通讯作者：
Munshi, Nikhil C.
中科院分区：
文献类型：
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作者：
Samur, Mehmet Kemal;Aktas Samur, Anil;Munshi, Nikhil C.
目的 多发性骨髓瘤 (MM) 伴有异质体细胞改变。本研究的总体目标是使用深度全基因组测序 (WGS) 描述骨髓瘤的基因组图谱，并开发一个识别长期生存患者的模型。 方法 我们分析了 IFM/DFCI 2009 研究中 183 名新诊断的 MM 患者的深度 WGS 数据，这些患者接受来那度胺、硼替佐米和地塞米松 (RVD) 单独治疗或 RVD + 自体干细胞移植 (ASCT) 治疗（ClinicalTrials.gov 标识符：NCT01191060）。我们将基因组标记与临床数据相结合。 结果 我们报告了 MM 亚组内突变负荷和过程的显着变异性。观察到的突变过程激活的时间线为骨髓瘤诊断时检测到的两种不同的突变变化获取模型提供了基础。事实上，所有 MM 亚组都已激活 DNA 修复相关特征作为重要的晚期突变过程，而针对 C>G 的 APOBEC 特征在高危 MM 疾病进展的中期被激活。重要的是，我们确定了一个基因组定义的 MM 亚组（占新诊断患者的 17%），具有低 DNA 损伤（低基因组疤痕评分，9 号染色体增益）和优异的结果（69 个月时总生存率为 100%），这在大型独立队列中得到了验证。该亚组使我们能够区分低风险和高风险的超二倍体 MM 患者，并确定无进展生存期延长的患者。该亚组的基因组特征包括较低的突变负荷，其中年龄相关突变以及频繁的 NRAS 突变具有显着贡献。令人惊讶的是，他们的总生存期与国际分期系统和微小残留病状态无关。结论这是一项全面的研究，旨在识别具有延长生存期的高危人群的基因组标记。该患者亚组的识别将影响未来的治疗算法和研究计划。 (C) 2020 美国临床肿瘤学会
PURPOSE Multiple myeloma (MM) is accompanied by heterogeneous somatic alterations. The overall goal of this study was to describe the genomic landscape of myeloma using deep whole-genome sequencing (WGS) and develop a model that identifies patients with long survival.METHODS We analyzed deep WGS data from 183 newly diagnosed patients with MM treated with lenalidomide, bortezomib, and dexamethasone (RVD) alone or RVD + autologous stem cell transplant (ASCT) in the IFM/DFCI 2009 study (ClinicalTrials.gov identifier: NCT01191060). We integrated genomic markers with clinical data.RESULTS We report significant variability in mutational load and processes within MM subgroups. The timeline of observed activation of mutational processes provides the basis for 2 distinct models of acquisition of mutational changes detected at the time of diagnosis of myeloma. Virtually all MM subgroups have activated DNA repair-associated signature as a prominent late mutational process, whereas APOBEC signature targeting C>G is activated in the intermediate phase of disease progression in high-risk MM. Importantly, we identify a genomically defined MM subgroup (17% of newly diagnosed patients) with low DNA damage (low genomic scar score with chromosome 9 gain) and a superior outcome (100% overall survival at 69 months), which was validated in a large independent cohort. This subgroup allowed us to distinguish patients with low- and high-risk hyperdiploid MM and identify patients with prolongation of progression-free survival. Genomic characteristics of this subgroup included lower mutational load with significant contribution from age-related mutations as well as frequent NRAS mutation. Surprisingly, their overall survival was independent of International Staging System and minimal residual disease status.CONCLUSION This is a comprehensive study identifying genomic markers of a good-risk group with prolonged survival. Identification of this patient subgroup will affect future therapeutic algorithms and research planning. (C) 2020 by American Society of Clinical Oncology