Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation

Abstract

We have addressed whether aberrant ongoing hypermutation can be detected in the proto-oncogenes PIM1, c-MYC, RhoH/TTF, PAX5, and the tumor-suppressor gene CD95 in primary central nervous system lymphomas (PCNSLs) derived from immunocompetent HIV-negative patients. Nine of 10 PCNSLs analyzed harbored somatic mutations in the PIM1, c-MYC, RhoH/TTF, and PAX5 genes, but not in the CD95 gene, with 8 tumors carrying alterations in at least 2 of these genes. Furthermore, ongoing aberrant mutation was evidenced in a subset of PCNSLs (2 of 3). Although most of the mutations corresponded to base pair substitutions, deletions were also present. The mean mutation frequency was approximately 60-fold lower for these genes compared with the values obtained for immunoglobulin genes in PCNSL. They were increased 2- to 5-fold compared with extracerebral diffuse large B-cell lymphoma (DLBCL). In summary, our data demonstrate aberrant somatic hypermutations at high frequency in the PIM1, PAX5, RhoH/TTF, and c-MYC genes in most PCNSLs. These findings may indicate a pathogenic role for aberrant somatic hypermutation in PCNSL development. In contrast, although mutations were detected in exon 9 of the CD95 gene, the lack of mutations in the 5' region provides no evidence for the CD95 gene as a target for aberrant somatic mutation.

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

“…50 FAS mutations, which may impair apoptosis, have been identified in 20% (2/10) PCNSL. 15 In 12p13.2, a 200-kb MCR of deletion was detected with one PCNSL showing biallelic loss; in another PCNSL, the pattern of imbalances suggested a deletion to have occurred before amplification of an allele. The deletions affected the ETV6 gene, which is frequently translocated in hematopoietic tumors.…”

“…15 For each tumor sample, a total of 500 ng DNA were processed according to the Affymetrix GeneChip Mapping 100k Assay Manual (Affymetrix, Santa Clara, CA, USA). Briefly, 250 ng of genomic DNA was digested with XbaI or HindIII and ligated to GeneChip Human Mapping 50k adaptors.…”

Comprehensive identification of proteins in Hodgkin lymphoma-derived Reed–Sternberg cells by LC-MS/MS

“…35 PIM1 has been shown to be involved in several hematopoietic cancers, and has recently been identified as a target of aberrant somatic hypermutation in diffuse large B-cell lymphomas. 35,36 Epstein-Barr virus (EBV) has been shown to induce the upregulation of PIM kinases which is thought to contribute to the ability of EBV to immortalize B cells and predispose them to malignant transformation. 37 ErbB-3 is a 148 kDa type I membrane receptor tyrosine kinase protein.…”

Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation

“…Eight cases of CLL (cases [1][2][3][4][5][6][7][8] showed no transformation during the clinical course of the disease, 13 cases (cases 9-21) developed RT and eight cases (cases [22][23][24][25][26][27][28][29] showed PLT. In seven cases of RT (cases 9-15), both CLL and DLBL samples were available for analysis.…”

“…[5][6][7][8][9] Aberrant somatic hypermutation is considered as a malfunction of somatic hypermutation (SHM), which is a physiological process in the immunoglobulin (Ig) variable genes of germinal center (GC) B-cells promoting affinity maturation. 10 Aberrant somatic hypermutation induces genomewide genetic instability by affecting multiple loci outside the Ig genes, including c-MYC, RhoH, Pax-5 and Pim-1 protooncogenes.…”