文章：

全外显子组分析揭示与免疫化疗治疗弥漫性大B细胞淋巴瘤结局相关的新型体细胞基因组变异

Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma

原文发布日期：2015-08-28

DOI: 10.1038/bcj.2015.69

类型: Original Article

开放获取: 是

英文摘要：

Lack of remission or early relapse remains a major clinical issue in diffuse large B-cell lymphoma (DLBCL), with 30% of patients failing standard of care. Although clinical factors and molecular signatures can partially predict DLBCL outcome, additional information is needed to identify high-risk patients, particularly biologic factors that might ultimately be amenable to intervention. Using whole-exome sequencing data from 51 newly diagnosed and immunochemotherapy-treated DLBCL patients, we evaluated the association of somatic genomic alterations with patient outcome, defined as failure to achieve event-free survival at 24 months after diagnosis (EFS24). We identified 16 genes with mutations, 374 with copy number gains and 151 with copy number losses that were associated with failure to achieve EFS24 (P<0.05). Except for FOXO1 and CIITA, known driver mutations did not correlate with EFS24. Gene losses were localized to 6q21-6q24.2, and gains to 3q13.12-3q29, 11q23.1-11q23.3 and 19q13.12-19q13.43. Globally, the number of gains was highly associated with poor outcome (P=7.4 × 10−12) and when combined with FOXO1 mutations identified 77% of cases that failed to achieve EFS24. One gene (SLC22A16) at 6q21, a doxorubicin transporter, was lost in 54% of EFS24 failures and our findings suggest it functions as a doxorubicin transporter in DLBCL cells.

摘要翻译： 

缺乏缓解或早期复发仍是弥漫性大B细胞淋巴瘤（DLBCL）的主要临床难题，约30%患者对标准治疗方案无效。虽然临床因素和分子特征可部分预测DLBCL预后，但仍需补充信息以识别高危患者，特别是那些最终可能适用于干预治疗的生物学因素。通过对51例新确诊且接受免疫化疗的DLBCL患者进行全外显子组测序，我们评估了体细胞基因组改变与患者预后的关联（定义为诊断后24个月无事件生存期未达标，EFS24）。研究发现16个基因突变、374个拷贝数增益和151个拷贝数缺失与EFS24未达标显著相关（P<0.05）。除FOXO1和CIITA外，已知驱动突变均与EFS24无相关性。基因缺失集中于6q21-6q24.2区域，增益集中于3q13.12-3q29、11q23.1-11q23.3及19q13.12-19q13.43区域。整体而言，拷贝数增益数量与不良预后高度相关（P=7.4×10−12），且与FOXO1突变结合可识别77%的EFS24未达标病例。位于6q21区域的阿霉素转运蛋白基因SLC22A16在54%的EFS24失败病例中存在缺失，我们的研究提示该基因在DLBCL细胞中具有阿霉素转运功能。

原文链接：

Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma