Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker.
Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker.
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DOI：
10.1038/bcj.2017.12
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发表时间：
2017-02-24
影响因子：
12.8
通讯作者：
Walker BA
中科院分区：
文献类型：
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作者：
Chavan SS;He J;Tytarenko R;Deshpande S;Patel P;Bailey M;Stein CK;Stephens O;Weinhold N;Petty N;Steward D;Rasche L;Bauer M;Ashby C;Peterson E;Ali S;Ross J;Miller VA;Stephens P;Thanendrarajan S;Schinke C;Zangari M;van Rhee F;Barlogie B;Mughal TI;Davies FE;Morgan GJ;Walker BA
本研究的目的是使用临床认证的测序面板在多发性骨髓瘤中识别预后标志物和治疗靶点。我们使用FoundationOne Heme panel对578例浆细胞肿瘤患者进行了靶向测序，并确定了临床相关异常和新的预后标志物。突变负荷与maf和增殖基因表达组相关，高突变负荷与不良预后相关。我们确定了多发性骨髓瘤中关键基因（包括CDKN 2C、RB 1、TRAF 3、BIRC 3和TP 53）中存在的纯合缺失，并且复发时双等位基因失活显著富集。CDKN 2C、TP 53、RB 1和t（4;14）的改变与不良预后相关。RB 1的改变主要是纯合性缺失，与复发和预后不良相关，多变量分析后，与其他遗传标记（包括t（4;14））无关。骨髓瘤中关键肿瘤抑制基因的双等位基因失活在复发时富集，特别是在RB 1、CDKN 2C和TP 53中，它们具有预后意义。
The purpose of this study is to identify prognostic markers and treatment targets using a clinically certified sequencing panel in multiple myeloma. We performed targeted sequencing of 578 individuals with plasma cell neoplasms using the FoundationOne Heme panel and identified clinically relevant abnormalities and novel prognostic markers. Mutational burden was associated with maf and proliferation gene expression groups, and a high-mutational burden was associated with a poor prognosis. We identified homozygous deletions that were present in multiple myeloma within key genes, including CDKN2C, RB1, TRAF3, BIRC3 and TP53, and that bi-allelic inactivation was significantly enriched at relapse. Alterations in CDKN2C, TP53, RB1 and the t(4;14) were associated with poor prognosis. Alterations in RB1 were predominantly homozygous deletions and were associated with relapse and a poor prognosis which was independent of other genetic markers, including t(4;14), after multivariate analysis. Bi-allelic inactivation of key tumor suppressor genes in myeloma was enriched at relapse, especially in RB1, CDKN2C and TP53 where they have prognostic significance.