我们对与曼特尔细胞淋巴瘤（MCL）复发相关的遗传异常，即变异和拷贝数变异（CNVs）的认知仍然有限。通过全外显子测序对25名MCL患者的诊断和标准免疫化疗失败后的首次复发进行了分析。在诊断和复发时最常见的变异包括六个基因：TP53、ATM、KMT2D、CCND1、SP140和LRP1B。在诊断和复发时最常见的CNVs包括TP53和CDKN2A/B的缺失以及PIK3CA的扩增。与诊断（n = 27）相比，患者在复发（n = 34）时的平均突变数显著增加。在复发时最常见的新检测到的变异，即LRP1B基因突变，与更高的突变负荷相关。TP53变异的等位基因频率从0.35增加到0.76。在复发时，预测的CNV的频率和长度显著增加，其中CDKN2A/B的缺失最常见。我们的数据表明，在复发时已经存在的耐药性MCL克隆在诊断时已经存在，并且已经被治疗所选择。我们观察到了DNA损伤应答途径（TP53和CDKN2A/B）的遗传异常富集，并且MCL的异质性显著增加。我们鉴定了LRP1B失活作为MCL复发的一个新的潜在驱动因子。© 2023 The Authors. 由Wiley Periodicals LLC出版的《American Journal of Hematology》发表。

Our knowledge of genetic aberrations, that is, variants and copy number variations (CNVs), associated with mantle cell lymphoma (MCL) relapse remains limited. A cohort of 25 patients with MCL at diagnosis and the first relapse after the failure of standard immunochemotherapy was analyzed using whole-exome sequencing. The most frequent variants at diagnosis and at relapse comprised six genes: TP53, ATM, KMT2D, CCND1, SP140, and LRP1B. The most frequent CNVs at diagnosis and at relapse included TP53 and CDKN2A/B deletions, and PIK3CA amplifications. The mean count of mutations per patient significantly increased at relapse (n = 34) compared to diagnosis (n = 27). The most frequent newly detected variants at relapse, LRP1B gene mutations, correlated with a higher mutational burden. Variant allele frequencies of TP53 variants increased from 0.35 to 0.76 at relapse. The frequency and length of predicted CNVs significantly increased at relapse with CDKN2A/B deletions being the most frequent. Our data suggest, that the resistant MCL clones detected at relapse were already present at diagnosis and were selected by therapy. We observed enrichment of genetic aberrations of DNA damage response pathway (TP53 and CDKN2A/B), and a significant increase in MCL heterogeneity. We identified LRP1B inactivation as a new potential driver of MCL relapse.© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.