Infrequent BCL10 Mutations in B‐Cell Non‐Hodgkin's Lymphomas

Abstract

The BCL10 gene was recently isolated from the breakpoint region of t(1;14)(p22;q32) in mucosaassociated lymphoid tissue (MALT) lymphomas. Somatic mutations of BCL10 were found in not only t(1;14)-bearing MALT lymphomas, but also a wide range of other tumors. To clarify the actual frequency and spectrum of BCL10 mutations in primary B-cell non-Hodgkin's lymphomas (NHL), we examined a total of 139 NHL cases comprising 25 with MALT lymphomas, 54 with follicular B-cell lymphomas (FCL), and 60 with diffuse large B-cell lymphomas (DLBL). Polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and sequencing analyses led to the identification of four nucleotide changes in FCL and one in DLBL. In contrast, no BCL10 mutations were found in our series of MALT lymphomas. While screening for mutations, we also found three polymorphic sequence variants at codons 5 and 213 and in intron 1 of the BCL10 gene. Our results strongly suggest that somatic mutations of BCL10, if they occur at all, are rare in B-cell NHLs and do not commonly contribute to their molecular pathogenesis. Key words: Chromosome translocation -Apoptosis -SSCP -Malignant lymphomaRecurrent chromosomal translocations are well recognized and have been extensively characterized in nodal Bcell lymphomas.1, 2) These translocations were found to involve and deregulate an impressive list of proto-oncogenes including BCL1, BCL2, BCL6, and c-myc. In contrast, data on the molecular genetic mechanisms underlying the pathogenesis of marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type are only now beginning to emerge. Recurrent abnormalities found in MALT lymphomas include trisomies of chromosomes 3, 7, 12, and 18, the t(1;14)(p22;q32), and the t(11;18)(q21;q21).3-9) The t(11;18) translocation is reported to be one of the most frequent and specific chromosomal translocations in MALT lymphomas 7-9) and a novel gene, named MALT1 or MLT, has recently been cloned by ourselves and others from the breakpoint of the t(11;18). [10][11][12] On the other hand, the frequency of the t(1;14) translocation is relatively low and this translocation appears to be characteristic of aggressive MALT lymphomas. 13)The BCL10 gene has been isolated from the breakpoint region of the t(1;14) in MALT lymphomas.14, 15) BCL10, also called CIPER or CARMEN, was found to be a cellular homolog of the equine herpesvirus-2 E10 gene: both contain an amino-terminal caspase recruitment domain (CARD), which is homologous to that found in several apoptotic molecules.14-17) By analogy to BCL2 involvement in follicular B-cell lymphomas (FCL), BCL10 was expected to be anti-apoptotic. In functional assays, however, wild-type BCL10 turned out to be pro-apoptotic. It is noteworthy that BCL10 in t(1;14)-bearing MALT lymphomas exhibited a variety of truncating mutations.14, 15) As expected, the truncated BCL10 was shown to lose its proapoptotic action and display a gain-of-function transforming activity, so that it is conceivable that such mutations may confer a surviva...

BCL10 Single Nucleotide Polymorphism and Its Association with CSF Dissemination of Primary Intracranial Germ Cell Tumors

“…The high incidence of the SNP in the Japanese population might be associated with high frequency of the intracranial germinomas in Japan. Besides the SNP in exon 1, other SNPs have been identified in other exons at various frequencies [25, 26, 31, 32, 40]. In our series, we detected another previously reported SNP in only one patient with a mixed GCT (C-to-T transition in codon 162, exon 3; Thr → Met).…”

“…However, subsequent studies failed to confirm the existence of frequent mutations [25,26,27,28,29,30,31,32], and we detected no inactivating mutations in our 10 PGs and 10 nongerminomatous GCTs. Rather, we identified a specific SNP (G-to-T transition in codon 5, exon 1; Ala → Ser) in 5 of 10 patients with PG and in one patient with a mixed GCT.…”

“…PCR was performed in a final volume of 10 µl containing 2 ng DNA, 50 m M KCl, 1.5 m M MgCl 2 , 10 m M TRIS-HCl, 200 µ M each dNTP, 0.1% gelatin, 5 pmol of each primer set, 10% DMSO, and 2.5 units of Taq polymerase. For exon 1, the touchdown protocol was used [31]. For the other exons, initial 3-min denaturation at 95°C was followed by 40 cycles of denaturation at 95°C for 30 s, annealing at 56°C for 40 s, and extension at 72°C for 40 s on a thermal cycler (480, Perkin-Elmer).…”

“…It is mutated in human MALT lymphoma, mesothelioma, and testicular GCTs [21,22,23,24]. It has been suggested that the frequency of the BCL10 gene mutation is low in several tumor types including testicular GCTs; instead, several specific single nucleotide polymorphisms (SNPs) in the gene have been identified [25,26,27,28,29,30,31,32]. To our knowledge, the issue of whether BCL10 gene mutations or SNPs have the higher incidence and whether SNPs are associated with the biological status of intracranial GCTs has not been resolved.…”

Mutation study of the BCL10 gene in lymphoma with both RNA and DNA

“…Some BCL10 gene abnormalities were proposed to be found only in RNA and not in genomic DNA, 4,5 but no previous studies investigated DNA and RNA at the same time. [4][5][6][7][8] To make the matter clear, we first analyzed the mutations of BCL10 RNA from 43 lymphomas, and for those lymphomas with RNA alterations we investigated the genomic DNA extracted from the same tumor and normal tissues from the same patients.…”