Comparative genome profiling across subtypes of low-grade B-cell lymphoma identifies type-specific and common aberrations that target genes with a role in B-cell neoplasia
Comparative genome profiling across subtypes of low-grade B-cell lymphoma identifies type-specific and common aberrations that target genes with a role in B-cell neoplasia
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DOI：
10.3324/haematol.12221
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发表时间：
2008-04-30
期刊：
影响因子：
10.1
通讯作者：
Cigudosa, Juan C.
中科院分区：
文献类型：
--
作者：
Ferreira, Bibiana, I;Garcia, Juan F.;Cigudosa, Juan C.
背景低度恶性B细胞淋巴瘤是一种异质性很强的肿瘤，其鉴别诊断常常因缺乏特定的细胞遗传学或分子特征而受到影响。我们的目的是寻找能够更好地对不同类型的淋巴瘤进行分子鉴定的基因组特征。设计和方法我们选择了87例低级别B细胞淋巴瘤标本，这些肿瘤在临床和细胞遗传学上明确诊断为：滤泡性、脾边缘区、结节缘区、淋巴浆细胞性、外套细胞、结外缘区MALT型淋巴瘤或B细胞慢性淋巴细胞白血病。所有样本都接受了相同的高分辨率基因组DNA分析(基于阵列的比较基因组杂交)：一个包含分布在整个基因组中的44000个探针的全基因组平台。结果80%的病例表现出基因组不平衡(缺失和扩增)，但这些不平衡在套细胞淋巴瘤中的发生率从100%到33%不等。总共定义了95个影响所有淋巴瘤亚型的新的基因组失衡。我们评估了基因组不稳定的范围，检测了亚型中不同的基因组不稳定模式。核因子kB(Rel和BCL11A的获得以及COMMD3、BIRC1、IKK1和NFKB2的丢失)、Polycomb组蛋白(BMI1的获得和PCGF6的缺失)、DNA修复检查点途径(涉及CDT1的16q24缺失)或与B细胞淋巴瘤发病有关的miRNA(MIRN15A、MIRN16-1)等特定途径都是这种基因组不稳定性的靶点。结论尽管所有亚型的淋巴瘤都有DNA的获得和丢失，但对其基因组图谱的分析表明，几乎每个亚型都有特异的异常和频繁的异常，这些异常是许多淋巴瘤类型普遍存在的。这些常见的异常针对在B细胞淋巴瘤发生中很重要的基因。
BackgroundLow-grade B-cell lymphomas are a very heterogeneous group of tumors, whose differential diagnosis is frequently compromised by the lack of specific cytogenetic or molecular features. Our objective was to search for genomic features that allow a better molecular identification of the different types of lymphoma studied.Design and MethodsWe selected a panel of 87 low-grade B-cell lymphoma tumor samples that were unambiguously diagnosed (clinically and cytogenetically) as: follicular, splenic marginal zone, nodal marginal zone, lymphoplasmacytic, mantle cell, extranodal marginal zone MALT-type lymphoma or B-cell chronic lymphocytic leukemia. All samples were subjected to the same high-resolution genomic DNA analysis (array-based comparative genomic hybridization): a whole genome platform that contained 44000 probes distributed across the genome. Genomic imbalances were recorded, compiled and analyzed.ResultsEighty percent of analyzed cases showed genomic imbalances (deletions and gain/amplifications) but the frequency of these imbalances ranged from 100% in mantle cell lymphomas to 33% in MALT lymphomas. A total of 95 new genomic imbalances affecting all lymphoma subtypes, were defined. We evaluated the extension of the genomic instability, detecting distinct patterns of genomic instability within subtypes. Specific pathways, such as nuclear factor kB (gains of REL and BCL11A, and losses of COMMD3, BIRC1, IKK1 and NFKB2), Polycomb group proteins (gain of BMI1 and deletion of PCGF6), DNA repair checkpoint pathways (deletion of 16q24 involving CDT1), or miRNA with a role in B-cell lymphoma pathogenesis (MIRN15A, MIRN16-1), were targeted by this genomic instability.ConclusionsAlthough all subtypes of lymphomas showed gains and losses of DNA, the analysis of their genomic profiles indicated that there are specific aberrations in almost every subtype as well as frequent aberrations that are common to a large number of lymphoma types. These common aberrations target genes that are important in B-cell lymphomagenesis.