CREBBP和SOCS1突变是弥漫性大B细胞淋巴瘤的独立预后因素：SAKK 38/07前瞻性临床试验队列的突变分析
Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38/07 prospective clinical trial cohort.
作者信息
Juskevicius Darius, Jucker David, Klingbiel Dirk, Mamot Christoph, Dirnhofer Stephan, Tzankov Alexandar
机构信息
Institute of Pathology, University of Basel and University Hospital Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland.
Swiss Group for Clinical Cancer Research (SAKK), Effingerstrasse 40, CH-3008, Bern, Switzerland.
出版信息
J Hematol Oncol. 2017 Mar 17;10(1):70. doi: 10.1186/s13045-017-0438-7.
BACKGROUND/PURPOSE: Recently, the mutational background of diffuse large B cell lymphoma (DLBCL) has been revealed, identifying specific genetic events that drive lymphomagenesis. However, the prognostic value of these mutations remains to be determined. Prognostic biomarkers in DLBCL are urgently needed, since the current clinical parameter-based factors (e.g., International Prognostic Index (IPI)) are insufficient, particularly in identifying patients with poor prognosis who might benefit from alternative treatments.
METHODS
We investigated the prognostic value of somatic mutations in DLBCL in a clinical trial (NCT00544219) patient cohort homogenously treated with six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP), followed by two cycles of R (R-CHOP-14). The primary endpoint was event-free survival (EFS) at 2 years. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Targeted high-throughput sequencing (HTS) of tumor genomic DNA was performed on all exons or hotspots of 68 genes frequently mutated in B cell lymphomas. Mutational data was correlated with the endpoints to identify prognostic associations.
RESULTS
Targeted HTS detected somatic mutations in 71/76 (93%) of investigated cases. The most frequently mutated genes were KMT2D, SOCS1, GNA13, and B2M. Survival analysis revealed that CREBBP- and EP300-mutated cases had significantly worse OS, PFS, and EFS. In addition, ATM mutations predicted worse outcomes for all three clinical endpoints in germinal center B cell-like DLBCL. In contrast, SOCS1 mutations were associated with better PFS. On multivariable analysis taken into account IPI and failure to achieve complete remission, CREBBP and EP300 mutations remained significant to predict worse OS, PFS, and EFS.
CONCLUSION
Targeted mutation analysis of a uniformly treated prospective clinical trial DLBCL cohort identifies tumor-based genetic prognostic markers that could be useful in the clinical management of such patients.
TRIAL REGISTRATION
ClinicalTrials.gov NCT00544219.
背景/目的：最近，弥漫性大B细胞淋巴瘤（DLBCL）的突变背景已被揭示，确定了驱动淋巴瘤发生的特定基因事件。然而，这些突变的预后价值仍有待确定。DLBCL中的预后生物标志物亟待发现，因为目前基于临床参数的因素（如国际预后指数（IPI））并不充分，特别是在识别可能从替代治疗中获益的预后不良患者方面。
方法
我们在一项临床试验（NCT00544219）患者队列中研究了DLBCL体细胞突变的预后价值，该队列均接受了六个周期的利妥昔单抗、环磷酰胺、羟基柔红霉素、长春新碱和泼尼松（R-CHOP）治疗，随后进行两个周期的R（R-CHOP-14）治疗。主要终点是2年无事件生存期（EFS）。次要终点包括无进展生存期（PFS）和总生存期（OS）。对肿瘤基因组DNA进行靶向高通量测序（HTS），检测B细胞淋巴瘤中68个频繁突变基因的所有外显子或热点区域。将突变数据与终点进行关联，以确定预后相关性。
结果
靶向HTS在76例研究病例中的71例（93%）检测到体细胞突变。最常突变的基因是KMT2D、SOCS1、GNA13和B2M。生存分析显示，CREBBP和EP300突变的病例的OS、PFS和EFS显著较差。此外，ATM突变预示生发中心B细胞样DLBCL的所有三个临床终点预后更差。相反，SOCS1突变与更好的PFS相关。在考虑IPI和未达到完全缓解的多变量分析中，CREBBP和EP300突变仍然是预测OS、PFS和EFS较差的显著因素。
结论
对一项接受统一治疗的前瞻性临床试验DLBCL队列进行靶向突变分析，确定了基于肿瘤的基因预后标志物，这些标志物可能有助于此类患者的临床管理。
试验注册
ClinicalTrials.gov NCT00544219。
Zotero 插件