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具有高基因组不稳定性的侵袭性套细胞淋巴瘤形态学变异型,表现为频繁的染色体重排、CDKN2A/B 缺失和 TP53 突变:一项多机构研究。

Aggressive morphologic variants of mantle cell lymphoma characterized with high genomic instability showing frequent chromothripsis, CDKN2A/B loss, and TP53 mutations: A multi-institutional study.

机构信息

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.

出版信息

Genes Chromosomes Cancer. 2020 Aug;59(8):484-494. doi: 10.1002/gcc.22849. Epub 2020 Apr 17.

Abstract

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.

摘要

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。

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