An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup
An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup
复制标题
DOI：
10.1182/blood-2013-06-507152
复制
发表时间：
2015-02-05
期刊：
影响因子：
20.3
通讯作者：
Steidl, Christian
中科院分区：
文献类型：
--
作者：
Chan, Fong Chun;Telenius, Adele;Steidl, Christian
弥漫性大B细胞淋巴瘤（DLBCL）的有效治疗受到标准治疗的异质性反应的困扰，淋巴瘤患者不良结局的分子机制仍然难以捉摸。在此，我们分析了利妥昔单抗加环磷酰胺、多柔比星、长春新碱和泼尼松龙（R-CHOP）治疗的DLBCL队列中的148个基因组和91个匹配的转录组，以揭示与治疗失败相关的分子亚组。高分辨率基因分型阵列和RNA测序数据的系统整合揭示了RCOR 1的新缺失与不利的无进展生存期相关（P = .001）。将来自临床样品的表达数据与来自淋巴瘤细胞系KM-H2和Raji中的RCOR 1敲低的数据整合，产生包含233个基因的RCOR 1丢失相关基因标记。该特征识别了总体生存率不利的患者亚组（P = 0.023）。233个基因标记对总生存期的预后意义在一个包括195名R-CHOP治疗患者的独立队列中重现（P = .039）。此外，我们发现在国际预后指数低风险组中，基因签名提供了独立于细胞来源表型的额外预后价值。我们提出了一个新的和可重复的DLBCL分子亚组，影响R-CHOP治疗DLBCL患者的风险分层，并揭示了一种可能的新途径的治疗干预策略。
Effective treatment of diffuse large B-cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in a DLBCL cohort treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA sequencing data revealed novel deletions in RCOR1 to be associated with unfavorable progression-free survival (P = .001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (P = .023). The prognostic significance of the 233-gene signature for overall survival was reproduced in an independent cohort comprising 195 R-CHOP-treated patients (P = .039). Additionally, we discovered that within the International Prognostic Index low-risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. We present a novel and reproducible molecular subgroup of DLBCL that impacts risk-stratification of R-CHOP-treated DLBCL patients and reveals a possible new avenue for therapeutic intervention strategies.