Department of Pathology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Department of Pathology, University of Chicago Hospitals, Chicago, Illinois, USA.
Genes Chromosomes Cancer. 2020 Aug;59(8):484-494. doi: 10.1002/gcc.22849. Epub 2020 Apr 17.
Aggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B/P-MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi-institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B/P-MCL, using next generation sequencing and SNP-array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C-MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B/P-MCL cases showed loss of CDKN2A/B (6 biallelic and 6 monoallelic losses); while only one C-MCL showed monoallelic CDKN2A/B loss. In B/P-MCL, TP53 was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored TP53 mutations. Other recurrent mutations in B/P-MCL included ATM (7, 53%), CCND1 (5, 38%), NOTCH1 (2, 18%), NOTCH2, and BIRC3 (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of CDKN2A/B and TP53 alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B/P-MCL may be an indicator of clinically aggressive MCL. In addition, frequent CDKN2A deletion and high genomic instability may provide potential targets for alternative treatment.
侵袭性套细胞淋巴瘤(MCL)的形态学变异型,包括母细胞样和多形性(B/P-MCL),较为罕见,与不良临床结局相关。这些变异型的基因组图谱尚未完全探索。在这项多机构研究中,我们通过下一代测序和 SNP 芯片,描述了 B/P-MCL 中的复发性突变和新的基因组拷贝数改变(CNAs)。染色体重排是一种最近描述的大规模染色体重排现象,在 13 例 B/P-MCL 病例中有 8 例(62%)中发现了染色体重排,并且还观察到高度的基因组复杂性,频繁出现拷贝数增益和丢失。相比之下,9 例传统 MCL(C-MCL)的对照队列未显示染色体重排且复杂性较低。13 例 B/P-MCL 中有 12 例(92%)显示 CDKN2A/B 缺失(6 例为双等位基因缺失,6 例为单等位基因缺失);而仅有 1 例 C-MCL 显示单等位基因 CDKN2A/B 缺失。在 B/P-MCL 中,TP53 是最常见的突变基因,有 8 例(62%)出现突变,其中 6 例同时存在 17p 染色体缺失。在有染色体重排的 8 例病例中,有 6 例(85%)存在 TP53 突变。B/P-MCL 中还存在其他复发性突变,包括 ATM(7 例,53%)、CCND1(5 例,38%)、NOTCH1(2 例,18%)、NOTCH2 和 BIRC3(各 3 例,23%)。在此,我们描述了与染色体重排相关的高度基因组不稳定性,以及在侵袭性 MCL 变体中 CDKN2A/B 和 TP53 改变的高频率。在 B/P-MCL 中观察到的非随机染色体重排事件可能是临床侵袭性 MCL 的一个指标。此外,频繁的 CDKN2A 缺失和高度的基因组不稳定性可能为替代治疗提供潜在靶点。