Park Ha Young, Lee Seung-Bok, Yoo Hae-Yong, Kim Seok-Jin, Kim Won-Seog, Kim Jong-Il, Ko Young-Hyeh
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Republic of Korea.
Department of Pathology, Samsung Medical Center, SungKyunKwan University, Seoul, 06351, Republic of Korea.
Oncotarget. 2016 Dec 27;7(52):86433-86445. doi: 10.18632/oncotarget.13239.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although rituximab therapy improves clinical outcome, some patients develop resistant DLBCL; however, the genetic alterations in these patients are not well documented. To identify the genetic background of refractory DLBCL, we conducted whole-exome sequencing and transcriptome sequencing for six patients with refractory and seven with responsive DLBCL. The average numbers of pathogenic somatic single nucleotide variants and indels in coding regions were 71 in refractory patients (range 28-120) and 38 (range 19-66) in responsive patients. Missense mutations of TP53 were exclusive in 50% (3/6) of refractory patients and involved the DNA-binding domain of TP53. All missense mutations of TP53 were accompanied by copy number deletions. RAB11FIP5, PRKCB, PRDM15, FNBP4, AHR, CEP128, BRE, DHX16, MYO6, and NMT1 mutations were recurrent in refractory patients. MYD88, B2M, SORCS3, and WDFY3 mutations were more frequent in refractory patients than in responsive patients. REL-BCL11A fusion was found in two refractory patients; one had both fusion and copy number gain. Recurrent copy gains of POU2AF1, SLC1A4, REL11, FANCL, CACNA1D, TRRAP, and CUX1 with significantly increased average expression were found in refractory patients. The expression profile revealed enriched gene sets associated with treatment resistance, including oxidative phosphorylation and ATP-binding cassette transporters. In conclusion, this study integrated both genomic and transcriptomic alterations associated with refractory DLBCL and found several treatment-resistance alterations that may contribute to refractoriness.
弥漫性大B细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤类型。尽管利妥昔单抗治疗可改善临床结局，但一些患者会发展为难治性DLBCL；然而，这些患者的基因改变尚未得到充分记录。为了确定难治性DLBCL的遗传背景，我们对6例难治性DLBCL患者和7例反应性DLBCL患者进行了全外显子测序和转录组测序。难治性患者编码区致病性体细胞单核苷酸变异和插入缺失的平均数量为71个（范围28 - 120），反应性患者为38个（范围19 - 66）。TP53的错义突变在50%（3/6）的难治性患者中是独有的，且涉及TP53的DNA结合结构域。TP53的所有错义突变均伴有拷贝数缺失。RAB11FIP5、PRKCB、PRDM15、FNBP4、AHR、CEP128、BRE、DHX16、MYO6和NMT1突变在难治性患者中反复出现。MYD88、B2M、SORCS3和WDFY3突变在难治性患者中比在反应性患者中更常见。在两名难治性患者中发现了REL - BCL11A融合；其中一名患者既有融合又有拷贝数增加。在难治性患者中发现了POU2AF1、SLC1A4、REL11、FANCL、CACNA1D、TRRAP和CUX1的反复拷贝数增加，且平均表达显著增加。表达谱显示与治疗耐药相关的基因集富集，包括氧化磷酸化和ATP结合盒转运体。总之，本研究整合了与难治性DLBCL相关的基因组和转录组改变，并发现了几种可能导致难治性的治疗耐药改变。
