Somatic mutation of the 5' noncoding region of the BCL-6 gene is associated with intraclonal diversity and clonal selection in histological transformation of follicular lymphoma.
Somatic mutation of the 5' noncoding region of the BCL-6 gene is associated with intraclonal diversity and clonal selection in histological transformation of follicular lymphoma.
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BCL-6 基因 5 非编码区的体细胞突变与滤泡性淋巴瘤组织学转化中的克隆内多样性和克隆选择相关。
DOI：
10.1016/s0002-9440(10)64969-3
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Matolcsy,A
中科院分区：
文献类型：
--
作者：
Szereday,Z;Csernus,B;Nagy,M;László,T;Warnke,RA;Matolcsy,A
滤泡性淋巴瘤是一种B细胞性非霍奇金淋巴瘤。这经常表现为t(14；18)易位。FL的克隆进化和组织学转化经常与继发性遗传改变的积累有关。已有研究表明，在相当一部分FL和弥漫性大细胞淋巴瘤(DLCL)中，bcl6基因可以通过染色体重排和5‘非编码区的突变而改变。为了阐明bcl6基因改变在FL的组织转化和克隆性进展中的作用，我们分析了12例FL患者的系列活检标本。2例FL二次活检未见组织学改变，10例FL二次活检有形态转化为DLCL。用Southern印迹法检测bcl6基因重排，聚合酶链式反应-单链构象多态分析和序列分析检测bcl6基因5‘非编码区突变，免疫组织化学方法检测bcl6蛋白表达。在所有样本中均未检测到bcl6基因重排，但在7例bcl6基因5‘非编码区共发现58个突变。5例FL和克隆性FL或DLCL均发生突变，2例仅DLCL样本发生突变。在未显示形态变化的多个FL活检标本中，突变是相同的。在FL细胞经历形态转化的6例患者中，观察到相当大的克隆内序列异质性，表明体细胞突变类型正在进行。基于共享和非共享突变的模式，可以建立肿瘤克隆的系谱关系。在所有这些病例中，FL的组织学转变与以bcl-6 5‘非编码序列中新的突变位点为标志的亚群的出现有关。在这六例中的三例中，组织学转化也与bcl6蛋白的表达减少有关。这些结果表明，bcl6基因5‘非编码区的突变是在FL的克隆性进化过程中发生的，在淋巴瘤进化的不同时间点上，不同的克隆型占主导地位。
Follicular lymphoma (FL) is a B cell non-Hodgkin's lymphoma (NHL. that frequently displays a t(14;18) translocation. Clonal evolution and histological transformation of FL is frequently associated with the accumulation of secondary genetic alterations. It has been demonstrated that the BCL-6 gene can be altered by chromosomal rearrangements and by mutations clustering in its 5′ noncoding region in a significant fraction of FL and diffuse large cell lymphoma (DLCL). To elucidate the role of the BCL-6 gene alterations in the histological transformation and clonal progression of FL, we analyzed serial biopsy specimens from 12 patients with FL. Two cases of FL showed no histological alteration in the second biopsy, and 10 cases of FL showed morphological transformation to DLCL in the second biopsy. Southern blot analysis was used to detect rearrangement of the BCL-6 gene, polymerase chain reaction-single strand conformation polymorphism and sequence analysis were performed for identification of mutations in the 5′ noncoding region of the BCL-6 gene, and immunohistochemical analysis was applied to reveal the BCL-6 protein expression. No BCL-6 gene rearrangement was detected in any of the samples, but a total of 58 mutations were found in the 5′ noncoding region of the BCL-6 gene in seven cases. In five cases, both the FL and the clonally related FL or DLCL, and in two cases only the DLCL samples were mutated. The mutations were identical in multiple biopsy specimens of FL that did not show morphological transformation. In six patients where FL cells underwent morphological transformation, considerable intraclonal sequence heterogeneity was observed, indicating an ongoing type of somatic mutation. Based on the pattern of shared and nonshared mutations, the genealogical relationship of neoplastic clones could be established. In all of these cases, the histological transformation of FL was associated with the emergence of a subpopulation marked by new sites of mutations in the BCL-6 5′ noncoding sequences. In three of these six cases, the histological transformation is also associated with the reduced expression of the BCL-6 protein. These findings demonstrate that mutation of the 5′ noncoding region of the BCL-6 gene developed in the clonal evolution of FL, and at different time points in the lymphoma evolution different clonotypes dominate.