Liso Arcangelo, Capello Daniela, Marafioti Teresa, Tiacci Enrico, Cerri Michaela, Distler Verena, Paulli Marco, Carbone Antonino, Delsol Georges, Campo Elias, Pileri Stefano, Pasqualucci Laura, Gaidano Gianluca, Falini Brunangelo
Institute of Hematology, University of Perugia, Policlinico, Monteluce, 06122 Perugia, Italy.
Blood. 2006 Aug 1;108(3):1013-20. doi: 10.1182/blood-2005-10-3949. Epub 2006 Apr 13.
Aberrant somatic hypermutation (SHM) has been identified as a mechanism for genomewide instability in diffuse large B-cell lymphoma (DLBCL). To assess whether aberrant SHM plays a role in the molecular pathogenesis of Hodgkin lymphoma (HL), we investigated microdissected neoplastic cells of nodular lymphocyte-predominant HL (NLPHL; n = 10) and classic HL (cHL; n = 9) for the presence of mutations in the 5' sequences of 4 previously identified aberrant SHM targets (PIM1, PAX5, RhoH/TTF, c-MYC). Mutations in one or more genes were detected in 80% of NLPHLs and 55% of cHLs, with 50% and 30% of patients carrying mutations in 2 or more genes, respectively. The most frequently involved protooncogene was PAX5, mutated in 7 of 9 patients with NLPHL and 2 of 9 patients with cHL. In total, 34 mutations were detected in NLPHL (frequency, 1.04/1,000 bp) and 35 were detected in patients with cHL (frequency, 1.92/1,000 bp). Mutations were of somatic origin because they were absent in control T cells and shared most of the features of the immunoglobulin variable (IGV) gene-associated SHM mechanism-ie, single nucleotide substitutions (n = 63) with rare deletions/insertions (n = 6) and a predominance of transitions over transversions with preferential targeting motifs. Our finding that NLPHL and cHL are targeted by aberrant SHM, as is DLBCL, suggests that these lymphomas may share common molecular pathogenetic events.
异常体细胞超突变（SHM）已被确定为弥漫性大B细胞淋巴瘤（DLBCL）全基因组不稳定的一种机制。为了评估异常SHM是否在霍奇金淋巴瘤（HL）的分子发病机制中起作用，我们研究了经显微切割的结节性淋巴细胞为主型HL（NLPHL；n = 10）和经典型HL（cHL；n = 9）的肿瘤细胞，以检测4个先前确定的异常SHM靶点（PIM1、PAX5、RhoH/TTF、c-MYC）5'序列中的突变情况。在80%的NLPHL和55%的cHL中检测到一个或多个基因的突变，分别有50%和30%的患者携带2个或更多基因的突变。最常受累的原癌基因是PAX5，在9例NLPHL患者中有7例发生突变，在9例cHL患者中有2例发生突变。在NLPHL中共检测到34个突变（频率为1.04/1000 bp），在cHL患者中检测到35个突变（频率为1.92/1000 bp）。这些突变是体细胞起源的，因为在对照T细胞中不存在，并且具有免疫球蛋白可变（IGV）基因相关SHM机制的大多数特征，即单核苷酸替换（n = 63），罕见的缺失/插入（n = 6），以及转换多于颠换并具有优先靶向基序。我们的研究发现，与DLBCL一样，NLPHL和cHL也受到异常SHM的靶向作用，这表明这些淋巴瘤可能共享共同的分子致病事件。
