Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression
Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression
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DOI：
10.1200/jco.20.00437
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发表时间：
2020-07-20
影响因子：
45.3
通讯作者：
Ghobrial, Irene M.
中科院分区：
文献类型：
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作者：
Bustoros, Mark;Sklavenitis-Pistofidis, Romanos;Ghobrial, Irene M.
假性多发性骨髓瘤(SMM)是多发性骨髓瘤(MM)的前驱状态，每年进展的风险为10%。风险分层有不同的预后模型；然而，这些模型仅基于临床指标。疾病进展为MM的基因组改变的发现可以改进当前的风险模型。方法：我们使用下一代测序技术对214名SMM患者进行了研究。我们对166个肿瘤进行了全外显子组测序，其中包括5个连续样本，并对48个肿瘤进行了深度靶向测序。结果我们观察到，通过SMM的诊断，大多数进展所需的基因改变已经获得。特别是，我们发现，在考虑临床风险分期后，丝裂原活化蛋白激酶途径(KRAS和NRAS单核苷酸变异[SNV])、DNA修复途径(缺失17P、TP53和ATM SNV)和MYC(易位或拷贝数变异)都是进展的独立危险因素。我们在一个外部SMM队列中验证了这些发现，表明具有这三个特征中的任何一个的患者进展到MM的风险更高。此外，APOBEC相关突变在进展的患者中丰富，并与我们队列中较短的进展时间相关。结论SMM是一个遗传成熟的实体，大多数驱动因素的基因改变已经发生，这表明存在从意义未知的单克隆性伽马病到MM的右倾遗传进化模型。我们确定并外部验证了进展的基因组预测因子，可以区分进展到MM的高风险患者，从而提高当前临床模型的精确度。
PURPOSESmoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models.METHODSWe used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors.RESULTSWe observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort.CONCLUSIONSMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.