Hersby Ditte Stampe, Schejbel Lone, Breinholt Marie Fredslund, Høgdall Estrid, Nørgaard Peter, Nielsen Torsten Holm, Pedersen Lars Møller, Gang Anne Ortved
Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
Department of Pathology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
Ann Hematol. 2024 Dec;103(12):5835-5848. doi: 10.1007/s00277-024-06108-w. Epub 2024 Dec 7.
Large B-cell lymphoma (LBCL) exhibits striking clinical and molecular heterogeneity. New approaches have emerged to explore tumor heterogeneity and classify LBCL into biological categories. Consequently, the informational requirements from diagnostic samples to provide the necessary information have increased, but the adequacy of single-site biopsies to provide such information is largely unknown. Here we describe spatial and temporal intra-patient variations in the mutational landscape of paired biopsies.
Paired biopsies from 30 patients with LBCL were obtained from spatially distinct sites at the time of primary diagnosis before treatment and/or at a subsequent relapse. The samples were sequenced using a custom designed 59-gene next generation sequencing (NGS) lymphoma panel.
Differences in detected mutations of pathogenic or likely pathogenic significance were frequent both when comparing paired diagnostic biopsies, 2/6 (33%), and when comparing paired biopsies at primary diagnosis and relapse, 8/16 (50%). Mutational heterogeneity tended to increase with longer time interval between biopsies. Analysis of paired diagnostic and relapse biopsies revealed that certain clones present at diagnosis disappeared, while new clones emerged at relapse. Notably, TP53 mutations were detected in six out of seven patients in an extranodal location. In two cases, TP53 mutation was only detected in the relapse biopsy. Several of the mutations identified in this study are used or under investigation as targets for cancer treatments.
Multi-site biopsies revealed spatial and temporal mutational heterogeneity in patients with LBCL. Our findings indicate that mutational differences between biopsy pairs can occur at all timepoints examined. This underscores the necessity of performing repeat biopsies with each relapse to capture the full spectrum of genetic aberrations.
大B细胞淋巴瘤（LBCL）表现出显著的临床和分子异质性。新的方法已经出现，用于探索肿瘤异质性并将LBCL分类为生物学类别。因此，从诊断样本中获取必要信息的信息需求增加了，但单部位活检提供此类信息的充分性在很大程度上尚不清楚。在这里，我们描述了配对活检的突变图谱在患者体内的空间和时间变化。
从30例LBCL患者中获取配对活检样本，这些样本来自治疗前初次诊断时和/或随后复发时空间上不同的部位。使用定制设计的59基因下一代测序（NGS）淋巴瘤检测板对样本进行测序。
在比较配对的诊断活检时，2/6（33%）的样本中检测到具有致病或可能致病意义的突变存在差异；在比较初次诊断和复发时的配对活检时，8/16（50%）的样本中存在差异。活检之间的时间间隔越长，突变异质性往往越高。对配对的诊断和复发活检进行分析发现，诊断时存在的某些克隆消失了，而复发时出现了新的克隆。值得注意的是，在7例患者中的6例结外部位检测到TP53突变。在2例病例中，仅在复发活检中检测到TP53突变。本研究中鉴定的几种突变被用作或正在研究作为癌症治疗的靶点。
多部位活检揭示了LBCL患者的空间和时间突变异质性。我们的研究结果表明，在所有检查的时间点，活检配对之间都可能出现突变差异。这强调了在每次复发时进行重复活检以捕捉全部遗传畸变谱的必要性。
