Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.
Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, USA.
ESMO Open. 2021 Feb;6(1):100012. doi: 10.1016/j.esmoop.2020.100012. Epub 2021 Jan 4.
The prognosis of patients with secondary central nervous system lymphoma (SCNSL) is poor and despite massive advances in understanding the mutational landscape of primary diffuse large B-cell lymphoma (DLBCL), the genetic comparison to SCNSL is still lacking. We therefore collected paired samples from six patients with DLBCL with available biopsies from a lymph node (LN) at primary diagnosis and the central nervous system (CNS) at recurrence.
A targeted, massively parallel sequencing approach was used to analyze 216 genes recurrently mutated in DLBCL. Healthy tissue from each patient was also sequenced in order to exclude germline mutations. The results of the primary biopsies were compared with those of the CNS recurrences to depict the genetic background of SCNSL and evaluate clonal evolution.
Sequencing was successful in five patients, all of whom had at least one discordant mutation that was not detected in one of their samples. Four patients had mutations that were found in the CNS but not in the primary LN. Discordant mutations were found in genes known to be important in lymphoma biology such as MYC, CARD11, EP300 and CCND3. Two patients had a Jaccard similarity coefficient below 0.5 indicating substantial genetic differences between the primary LN and the CNS recurrence.
This analysis gives an insight into the genetic landscape of SCNSL and confirms the results of our previous study on patients with systemic recurrence of DLBCL with evidence of substantial clonal diversification at relapse in some patients, which might be one of the mechanisms of treatment resistance.
继发中枢神经系统淋巴瘤（SCNSL）患者的预后较差，尽管人们对原发性弥漫性大 B 细胞淋巴瘤（DLBCL）的突变景观有了大量了解，但与 SCNSL 的基因比较仍然缺乏。因此，我们从 6 名 DLBCL 患者中收集了配对样本，这些患者在初次诊断时有淋巴结（LN）活检，在复发时有中枢神经系统（CNS）活检。
采用靶向、大规模平行测序方法分析了 216 个在 DLBCL 中经常发生突变的基因。为了排除种系突变，还对每位患者的健康组织进行了测序。将原发活检的结果与 CNS 复发的结果进行比较，以描绘 SCNSL 的遗传背景并评估克隆进化。
测序在五名患者中均成功，所有患者均至少有一个在其中一个样本中未检测到的不一致突变。四名患者的 CNS 中存在但在原发 LN 中不存在的突变。不一致的突变发生在 MYC、CARD11、EP300 和 CCND3 等已知对淋巴瘤生物学很重要的基因中。两名患者的 Jaccard 相似系数低于 0.5，表明原发 LN 和 CNS 复发之间存在显著的遗传差异。
这项分析深入了解了 SCNSL 的遗传特征，并证实了我们之前对 DLBCL 全身复发患者的研究结果，这些结果表明在一些患者中复发时存在实质性的克隆多样化，这可能是治疗耐药的机制之一。
