Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma
Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma
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DOI：
10.1182/blood-2002-11-3606
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发表时间：
2003-09-01
期刊：
影响因子：
20.3
通讯作者：
Dalla-Favera, R
中科院分区：
文献类型：
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作者：
Gaidano, G;Pasqualucci, L;Dalla-Favera, R
艾滋病相关非霍奇金淋巴瘤（AIDS-NHL）的发病机制与染色体易位有关，这些易位使各种癌基因的表达失调。最近，一种新的遗传损伤机制，称为异常超突变，已被确定在弥漫性大B细胞淋巴瘤（DLBCL）的免疫功能正常的主机。在这些肿瘤中，通常靶向B细胞中的免疫球蛋白V（IgV）基因的体细胞超突变（SHM）过程似乎失败并导致多种原癌基因（包括PIM-1、PAX-5、RhoH/TTF和c-MYC）的5'序列突变。为了研究AIDS-NHL是否也发生异常超突变，我们研究了这4个基因在不同组织学亚型中的突变谱。在39例AIDS-NHL中，19例（46.7%）检测到1个或更多基因突变（18例AIDS-弥漫性大B细胞淋巴瘤中10例; 11例AIDS-Burkitt淋巴瘤中4例; 6例AIDS-原发性渗出性淋巴瘤中4例; 4例AIDS-原发性中枢神经系统淋巴瘤中1例），其中9例（23.1%）携带2个或更多基因突变。总体而言，PIM-1在5/39（12.8%）中突变，PAX-5在8/39（20.5%）中突变，RhoH/TTF在9/39（23.1%）中突变，c-MYC在7/27（25.9%）AIDS-NHL病例中突变。突变主要表现为单碱基对取代（n=63），罕见的缺失/插入（n=5），并显示出典型的IgV相关SHM过程的特征。此外，发现PIM-1和c-MYC中的许多突变影响编码外显子，导致可能具有功能后果的氨基酸取代。克隆内异质性分析证明，至少在某些病例中，异常超突变活性可能正在进行。这些数据表明，异常超突变与各种亚型的艾滋病-NHL，并可能代表其发病机制的主要贡献者。
The pathogenesis of AIDS-related non-Hodgkin lymphomas (AIDS-NHLs) is associated with chromosomal translocations that deregulate the expression of various oncogenes. Recently, a novel mechanism of genetic lesion, termed aberrant hypermutation, has been identified in diffuse large B-cell lymphoma (DLBCL) of immunocompetent hosts. In these tumors, the somatic hypermutation (SHM) process that normally targets immunoglobulin V (IgV) genes in B cells appears to misfire and causes mutations in the 5' sequences of multiple proto-oncogenes, including PIM-1, PAX-5, RhoH/TTF, and c-MYC. To investigate whether aberrant hypermutation occurs also in AIDS-NHL, we studied the mutation profile of these 4 genes in various histologic subtypes. Mutations in 1 gene or more were detected in 19 of 39 (46.7%) AIDS-NHL cases (10 of 18 AIDS-diffuse large B-cell lymphoma; 4 of 11 AIDS-Burkitt lymphoma; 4 of 6 AIDS-primary effusion lymphoma; 1 of 4 AIDS-primary central nervous system lymphoma), with 9 of 39 (23.1%) cases carrying mutations in 2 or more genes. Overall, PIM-1 was mutated in 5 of 39 (12.8%), PAX-5 in 8 of 39 (20.5%), RhoH/TTF in 9 of 39 (23.1%), and c-MYC in 7 of 27 (25.9%) AIDS-NHL cases. Mutations were represented mainly by single base pair substitutions (n=63) with rare deletions/insertions (n=5) and displayed features typical of the IgV-associated SHM process. In addition, a number of mutations in PIM-1 and c-MYC were found to affect coding exons, leading to amino acid substitutions with likely functional consequences. Analysis of intraclonal heterogeneity documented that the aberrant hypermutation activity may be ongoing in at least some cases. These data indicate that aberrant hypermutation is associated with various subtypes of AIDS-NHL and may represent a major contributor to their pathogenesis.