Nijland Marcel, Seitz Annika, Terpstra Martijn, van Imhoff Gustaaf W, Kluin Philip M, van Meerten Tom, Atayar Çiğdem, van Kempen Léon C, Diepstra Arjan, Kok Klaas, van den Berg Anke
Department of Hematology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
Cancers (Basel). 2018 Nov 20;10(11):459. doi: 10.3390/cancers10110459.
Current genomic models in diffuse large B-cell lymphoma (DLBCL) are based on single tumor biopsies, which might underestimate heterogeneity. Data on mutational evolution largely remains unknown. An exploratory study using whole exome sequencing on paired (primary and relapse) formalin fixed paraffin embedded DLBCL biopsies ( = 14) of 6 patients was performed to globally assess the mutational evolution and to identify gene mutations specific for relapse samples from patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. A minority of the mutations detected in the primary sample (median 7.6%, range 4.8⁻66.2%) could not be detected in the matching relapse sample. Relapsed DLBCL samples showed a mild increase of mutations (median 12.5%, range 9.4⁻87.6%) as compared to primary tumor biopsies. We identified 264 genes possibly related to therapy resistance, including tyrosine kinases ( = 18), (transmembrane) glycoproteins ( = 73), and genes involved in the JAK-STAT pathway ( = 7). Among the potentially resistance related genes were , , and , which have been reported to convey a risk for treatment failure. In conclusion, we show modest temporal heterogeneity between paired tumor samples with the acquisition of new mutations and identification of genes possibly related to therapy resistance. The mutational evolution could have implications for treatment decisions and development of novel targeted drugs.
弥漫性大B细胞淋巴瘤（DLBCL）目前的基因组模型基于单一肿瘤活检，这可能会低估异质性。关于突变演变的数据在很大程度上仍然未知。我们进行了一项探索性研究，对6例患者的配对（原发性和复发性）福尔马林固定石蜡包埋的DLBCL活检样本（n = 14）进行全外显子组测序，以全面评估突变演变，并识别接受利妥昔单抗、环磷酰胺、阿霉素、长春新碱和泼尼松龙治疗的患者复发样本特有的基因突变。在原发性样本中检测到的少数突变（中位数7.6%，范围4.8⁻66.2%）在匹配的复发样本中未被检测到。与原发性肿瘤活检相比，复发性DLBCL样本的突变略有增加（中位数12.5%，范围9.4⁻87.6%）。我们鉴定出264个可能与治疗耐药相关的基因，包括酪氨酸激酶（n = 18）、（跨膜）糖蛋白（n = 73）以及参与JAK-STAT途径的基因（n = 7）。在潜在的耐药相关基因中有NRAS、KRAS和BRAF，据报道这些基因会带来治疗失败的风险。总之，我们显示配对肿瘤样本之间存在适度的时间异质性，出现了新的突变并鉴定出可能与治疗耐药相关的基因。突变演变可能对治疗决策和新型靶向药物的开发产生影响。
