Characteristic Chromosomal Imbalances in Primary Central Nervous System Lymphomas of the Diffuse Large B‐Cell Type

Abstract

We performed a genome wide screening for genomic alterations on a series of 19 sporadic primary central nervous system lymphomas (PCNSL) of the diffuse large B-cell type by comparative genomic hybridization (CGH). The tumors were additionally analyzed for amplification and rearrangement of the BCL2 gene at 18q21 as well as for mutation of the recently cloned BCL10 gene at 1p22. Eighteen tumors showed genomic imbalances on CGH analysis. On average, 2.1 losses and 4.7 gains were detected per tumor. The chromosome arm most frequently affected by losses of genomic material was 6q (47%) with a commonly deleted region mapping to 6q21-q22. The most frequent gains involved chromosome arms 12q (63%), 18q and 22q (37% each), as well as 1q, 9q, 11q, 12p, 16p and 17q (26% each). High-level amplifications were mapped to 9p23-p24 (1 tumor) and to 18q21-q23 (2 tumors). However, PCR-based analysis, Southern blot analysis and high-resolution matrix-CGH of the BCL2 gene revealed neither evidence for amplification nor for genetic rearrangement. Mutational analysis of BCL10 in 16 PCNSL identified four distinct sequence polymorphisms but no mutation. Taken together, our data do not support a role of BCL2 rearrangement/ amplification and BCL10 mutation in PCNSL but indicate a number of novel chromosomal regions that likely carry yet unknown tumor suppressor genes or proto-oncogenes involved in the pathogenesis of these tumors.

Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma

“…29,30 Ten (53%) PCNSL showed a deletion involving 6q21, being in accordance with data reported previously. 7,10 The chromosomal region 6q21 is frequently deleted in various B-cell malignancies, including DLBCL, mantle cell lymphoma, acute lymphatic leukemia and immunoblastic lymphoma. 7,[31][32][33][34][35] This region has been suggested to harbor a tumor suppressor gene.…”

“…7 Furthermore, deletion of 6q was reported in 47% (9/19) PCNSL. 7 Finally, deletion of the human leukocyte antigen (HLA) class II region in 6p21.32 including homozygous loss was reported to affect more than half of all PCNSL and to be associated with loss of MHC expression. [10][11][12] Although these studies provided interesting and important insights into the genetic abnormalities in PCNSL, they were limited by a low resolution and the inability to detect partial uniparental disomy (pUPD).…”

“…5 High-level amplifications were mapped to 18q21-23 by comparative genomic hybridization to chromosomes in two tumors of a series of 19 PCNSL. 7 In addition, gains of 12q (63%, 12/19), 1q, 9q, 16p, and 17q (26% each, 5/19) were identified by comparative genomic hybridization and/or FISH. 7 Furthermore, deletion of 6q was reported in 47% (9/19) PCNSL.…”

“…7 In addition, gains of 12q (63%, 12/19), 1q, 9q, 16p, and 17q (26% each, 5/19) were identified by comparative genomic hybridization and/or FISH. 7 Furthermore, deletion of 6q was reported in 47% (9/19) PCNSL. 7 Finally, deletion of the human leukocyte antigen (HLA) class II region in 6p21.32 including homozygous loss was reported to affect more than half of all PCNSL and to be associated with loss of MHC expression.…”

“…[5][6][7] In addition to translocations of the immunoglobulin (IG) and the BCL6 loci present in a subset of PCNSL, gains and losses of genetic material are recurrent in PCNSL. 8,9 Gains of 18q were the most frequent alteration (38%) in one series of 13 PCNSL analyzed by interphase fluorescence in situ hybridization (FISH).…”