Otto Claudia, Scholtysik René, Schmitz Roland, Kreuz Markus, Becher Claudia, Hummel Michael, Rosenwald Andreas, Trümper Lorenz, Klapper Wolfram, Siebert Reiner, Küppers Ralf
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany.
Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.
Genes Chromosomes Cancer. 2016 Dec;55(12):932-943. doi: 10.1002/gcc.22391. Epub 2016 Jul 12.
Chromosomal translocations involving an immunoglobulin (IG) locus and a proto-oncogene play a major role in diffuse large B-cell lymphoma (DLBCL) pathogenesis. Recurrent IG translocation partners in DLBCL are the BCL6, BCL2, and MYC genes, but other rare translocation partners are also known. We studied 20 DLBCL with fluorescence in situ hybridization-based evidence for IG heavy chain (IGH) locus-associated translocations not involving BCL6, BCL2, MALT1, or MYC by long distance inverse PCR to identify the translocation partners. Moreover, we studied eight DLBCL with MYC translocations not involving IG or known non-IG loci as translocation partner to search for novel MYC translocations. We identified three novel IGH-associated translocations. Chromosomal breakpoints involved the IMMP2L gene in 7q31, the BCAS2 gene in 1p13, and the PVRL2 gene in 19q13. The latter gene, which is recurrently translocated in T-cell lymphomas, is significantly higher expressed in the biopsy with the translocation compared to cases without this genetic aberration, indicating a pathogenetic role of PVRL2 also in DLBCL. In one case with a MYC break we obtained a novel MYC-SOCS1 translocation representing an unusual translocation of a proto-oncogene with a tumor suppressor gene. Indeed, we demonstrate that the oncogene was deregulated and the tumor suppressor gene inactivated. As both genes undergo aberrant somatic hypermutation in the region of the chromosomal breakpoints, this translocation likely happened as a byproduct of the hypermutation process. Overall, our study suggests that chromosomal translocations in DLBCL are more heterogeneous than previously known. © 2016 Wiley Periodicals, Inc.
涉及免疫球蛋白（IG）基因座和原癌基因的染色体易位在弥漫性大B细胞淋巴瘤（DLBCL）发病机制中起主要作用。DLBCL中常见的IG易位伙伴是BCL6、BCL2和MYC基因，但也已知其他罕见的易位伙伴。我们通过长距离反向PCR研究了20例DLBCL，这些病例基于荧光原位杂交有证据表明存在与IG重链（IGH）基因座相关的易位，但不涉及BCL6、BCL2、MALT1或MYC，以鉴定易位伙伴。此外，我们研究了8例有MYC易位但不涉及IG或已知非IG基因座作为易位伙伴的DLBCL，以寻找新的MYC易位。我们鉴定出三种新的IGH相关易位。染色体断点涉及7q31的IMMP2L基因、1p13的BCAS2基因和19q13的PVRL2基因。后一个基因在T细胞淋巴瘤中经常发生易位，与没有这种基因畸变的病例相比，在有易位的活检组织中表达显著更高，表明PVRL2在DLBCL中也具有致病作用。在1例有MYC断裂的病例中，我们获得了一种新的MYC-SOCS1易位，这代表了原癌基因与肿瘤抑制基因的异常易位。事实上，我们证明了癌基因失调而肿瘤抑制基因失活。由于这两个基因在染色体断点区域都经历了异常的体细胞超突变，这种易位可能是超突变过程的副产物。总体而言，我们的研究表明DLBCL中的染色体易位比以前所知的更加异质。©2016威利期刊公司
