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首页> 美国卫生研究院文献>Journal of the Boston Society of Medical Sciences >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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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

机译：BCL-6基因5非编码区的体细胞突变与滤泡性淋巴瘤的组织学转化相关的克隆内多样性和克隆选择。

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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.
机译：滤泡性淋巴瘤（FL）是B细胞非霍奇金淋巴瘤（NHL），经常表现出t（14; 18）易位。 FL的克隆进化和组织学转化通常与次级遗传改变的积累有关。已经证明，BCL-6基因可以通过染色体重排和在其大部分的FL和弥漫性大细胞淋巴瘤（DLCL）中的5'非编码区中聚集的突变来改变。为了阐明BCL-6基因改变在FL的组织学转化和克隆进展中的作用，我们分析了12例FL患者的系列活检标本。在第二次活检中有2例FL没有表现出组织学改变，在第二次活检中有10例FL发生了形态学转变为DLCL。用Southern印迹分析检测BCL-6基因的重排，进行聚合酶链反应-单链构象多态性和序列分析以鉴定BCL-6基因5'非编码区的突变，并进行免疫组化分析揭示BCL-6蛋白表达。在任何样品中均未检测到BCL-6基因重排，但在7例中，在BCL-6基因的5'非编码区中发现了总共58个突变。在5种情况下，FL和克隆相关的FL或DLCL都发生了突变，在两种情况下，仅DLCL样本发生了突变。在FL的多个活检标本中，这些突变是相同的，未显示出形态学转化。在6例FL细胞进行了形态学转化的患者中，观察到大量的克隆内序列异质性，表明正在进行的体细胞突变类型。基于共有和非共有突变的模式，可以建立赘生性克隆的族谱关系。在所有这些情况下，FL的组织学转化与以BCL-6 5'非编码序列中新的突变位点标记的亚群的出现有关。在这六个案例中的三个案例中，组织学转化还与BCL-6蛋白表达降低有关。这些发现表明，在FL的克隆进化中发展了BCL-6基因的5'非编码区的突变，并且在淋巴瘤进化的不同时间点，不同的克隆型占主导。

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