文章：

使用临床检测方法对弥漫性大B细胞淋巴瘤进行整合的DNA/RNA靶向基因组分析

Integrated DNA/RNA targeted genomic profiling of diffuse large B-cell lymphoma using a clinical assay

原文发布日期：2018-06-12

DOI: 10.1038/s41408-018-0089-0

类型: Article

开放获取: 是

英文摘要：

We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma). Median number of GAs per case was 6, with 97% of patients harboring at least one alteration. Recurrent GAs were detected in genes with established roles in DLBCL pathogenesis (e.g. MYD88, CREBBP, CD79B, EZH2), as well as notable differences compared to prior studies such as inactivating mutations in TET2 (5%). Less common GAs identified potential targets for approved or investigational therapies, including BRAF, CD274 (PD-L1), IDH2, and JAK1/2. TP53 mutations were more frequently observed in relapsed/refractory DLBCL, and predicted for lack of response to first-line chemotherapy, identifying a subset of patients that could be prioritized for novel therapies. Overall, 90% (n = 169) of the patients harbored a GA which could be explored for therapeutic intervention, with 54% (n = 107) harboring more than one putative target.

摘要翻译： 

我们旨在利用福尔马林固定石蜡包埋（FFPE）活检标本描绘弥漫大B细胞淋巴瘤（DLBCL）的基因组图谱。采用针对血液系统恶性肿瘤相关基因的靶向测序技术，覆盖405个基因的DNA编码区、31个基因的非编码区及265个基因的RNA编码区（FoundationOne-Heme检测平台）。分析了短变异、基因重排和拷贝数变异。研究纳入198例样本（包括114例原发DLBCL、58例经治病例及26例滤泡性淋巴瘤大细胞转化）。每例样本中位基因改变数为6个，97%的患者携带至少一种基因改变。除发现DLBCL发病机制中已知的复发基因改变（如MYD88、CREBBP、CD79B、EZH2）外，还观察到与既往研究的显著差异，例如TET2失活突变率达5%。较少见的基因改变揭示了已获批或研发中疗法的潜在靶点，包括BRAF、CD274（PD-L1）、IDH2和JAK1/2。TP53突变在复发/难治性DLBCL中更常见，且预示对一线化疗无应答，这为优先接受新型疗法的人群筛选提供了依据。总体而言，90%（n=169）的患者存在可用于治疗干预探索的基因改变，其中54%（n=107）携带不止一个潜在治疗靶点。

原文链接：

Integrated DNA/RNA targeted genomic profiling of diffuse large B-cell lymphoma using a clinical assay