Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant disorder featuring familial clustering of colorectal and/or endometrial cancer, and other malignancies. Except for a rare case report, Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) have not been considered part of HNPCC. Recent murine models for HNPCC have shown an increased incidence of B- and T-cell lymphoma, as well as tumors of the gastrointestinal tract and other organ systems, involving defects in genes resulting in faulty mismatch repair (MMR) of DNA. These MMR genes include MLH1, MSH2, MSH3, MSH6, PMS1 and PMS2. We sought to analyze the occurrence of NHL and HD in families with clusters of colorectal cancers (CRC). Probands from 21 kindreds were classified as HNPCC (3), HNPCC-like (5), and HNPCC-variant (13); seen and followed by Clinical Genetics at Memorial Hospital the kindreds were assessed for the occurrence of NHL or HD. Of the 21 pedigrees, a total of 37 patients were identified who were diagnosed with leukemia, lymphoma, or HD. Fourteen of the 37 patients with a diagnosis of NHL or HD were further classified and showed varying histologies ranging from chronic lymphocytic leukemia/small lymphocytic lymphoma (2), mycosis fungoides (1), follicular lymphoma (1), extranodal marginal zone lymphoma of MALT type (2), diffuse large B-cell lymphoma (4), nodular sclerosis HD (3), and mixed cellularity HD (1). Microsatellite instability studies were performed on 6 cases but none showed evidence of replication error repair defects. Immunohistochemical stains performed on paraffin sections from these 6 representative cases showed differential protein expression of MLH1, MSH2, MSH6, and PMS2 when compared to normal reactive tissues from the same patient but showed no significant differences when compared to controls of non-familial, sporadic lymphomas. These results suggest that lymphomas arising in the setting of familial CRC do not bear the molecular hallmarks of HNPCC. Further studies are needed to explain the differential patterns of expression of RER-associated proteins in lymphomas, as well as the association of lymphomas and possibly renal cell cancers in a subset of kindreds in which CRC clustering is evident.
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PMID:Analysis of mismatch repair defects in the familial occurrence of lymphoma and colorectal cancer. 1240 Jun 5

It has been hypothesized that defects in DNA-mismatch repair are associated with smoking in certain types of transformed non-Hodgkin lymphoma (NHL). We have analyzed biopsy samples from two indolent B-cell lymphomas, follicular lymphoma (FL) and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), that have transformed to diffuse-large B-cell lymphoma (DLBCL). We correlated the presence or absence of DNA-mismatch repair enzymes by immunostaining as well as the p53 status to smoking history. Of all patients (n = 30), 37% showed negative immunostaining of MLH1, 16% showed negative immunostaining of MSH2 and 63% had p53 mutations and/or protein expression. Eighteen out of 20 transformed follicular lymphomas and seven out of 10 CLL/SLL that have transformed to DLBCL (Richter's syndrome) were informative for smoking histories. We found that the relative risk of negative immunostaining for either MLH1 or MSH2 was 2.2 times higher in smokers than non-smokers (relative risk = 2.2041, 95% confidence interval: 0.89714, 5.41491). No direct correlation was found between smoking and the mutations in the p53 gene. These results suggest that cigarette smoking may play a role in the development of transformed lymphomas through defective mismatch repair.
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PMID:Expression of DNA mismatch repair proteins in transformed non-Hodgkin's lymphoma: relationship to smoking. 1706 78

In Helicobacter pylori gastritis, constant antigenic stimulation triggers a sustained B-cell proliferation. Errors made during this continuous DNA replication are supposed to be corrected by the DNA mismatch repair mechanism. Failure of this mismatch repair mechanism has been described in hereditary non-polyposis colorectal cancer (HNPCC) and results in a replication error phenotype. Inherent to their instability during replication, microsatellites are the best markers of this replication error phenotype. We aimed to evaluate the role of defects in the DNA mismatch repair (MMR) mechanism and microsatellite instability (MSI) in relation to the most frequent genetic anomaly, translocation t(11;18)(q21;q21), in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we examined 10 microsatellite loci (BAT25, BAT26, D5S346, D17S250, D2S123, TGFB, BAT40, D18S58, D17S787 and D18S69) for instability in 28 patients with MALT lymphomas. In addition, these tumors were also immunostained for MLH1, MSH2, MSH6 and PMS2, as well as screened for the presence of t(11;18)(q21;q21) by real-time polymerase chain reaction (RT-PCR). We found MSI in 5/28 (18%) lymphomas, with MSI occurring in both t(11;18)(q21;q21)-positive and -negative tumors. One tumor displayed high levels of instability, and, remarkably, this was the only case displaying features of a diffuse large B-cell lymphoma. All microsatellite unstable lymphomas showed a loss of MSH6 expression. In conclusion, our data suggest that a MMR-defect may be involved in the development of gastric MALT lymphomas, and that a defect of MSH6 might be associated with those MSI-driven gastric lymphomas.
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PMID:Analysis of microsatellite instability in gastric mucosa-associated lymphoid tissue lymphoma. 2291 37

To further unravel the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL), we performed high-resolution comparative genomic hybridization on lymph node biopsies from 70 patients. With this strategy, we identified microdeletions of genes involved in the mutation mismatch repair (MMR) pathway in two samples. The first patient presented with a homozygous deletion of MSH2-MSH6 due to duplication of an unbalanced pericentric inversion of chromosome 2. The other case showed a PMS2 heterozygous deletion. PMS2 and MSH2-MSH6 abnormalities, respectively, resulted in a decrease and complete loss of gene expression. However, unlike tumors associated with the hereditary non-polyposis colorectal cancer syndrome or immunodeficiency-related lymphomas, no microsatellite instability was detected. Mutational profiles revealed especially in one patient an aberrant hypermutation without a clear activation-induced cytidine deaminase signature, indicating a breakdown of the high-fidelity repair in favor of the error-prone repair pathway. Our findings suggest that in a rare subset of patients, inactivation of the genes of the MMR pathway is likely an important step in the molecular pathogenesis of DLBCL and does not involve the same molecular mechanisms as other common neoplasms with MMR deficiency.
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PMID:Mutation mismatch repair gene deletions in diffuse large B-cell lymphoma. 2306 52

DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis.
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PMID:DNA repair genes are selectively mutated in diffuse large B cell lymphomas. 2396 Jan 88

Somatic hypermutation and class-switch recombination of the immunoglobulin (Ig) genes occur in germinal center (GC) B cells and are initiated through deamination of cytidine to uracil by activation-induced cytidine deaminase (AID). Resulting uracil-guanine mismatches are processed by uracil DNA glycosylase (UNG)-mediated base-excision repair and MSH2-mediated mismatch repair (MMR) to yield mutations and DNA strand lesions. Although off-target AID activity also contributes to oncogenic point mutations and chromosome translocations associated with GC and post-GC B-cell lymphomas, the role of downstream AID-associated DNA repair pathways in the pathogenesis of lymphoma is unknown. Here, we show that simultaneous deficiency of UNG and MSH2 or MSH2 alone causes genomic instability and a shorter latency to the development of BCL6-driven diffuse large B-cell lymphoma (DLBCL) in a murine model. The additional development of several BCL6-independent malignancies in these mice underscores the critical role of MMR in maintaining general genomic stability. In contrast, absence of UNG alone is highly protective and prevents the development of BCL6-driven DLBCL. We further demonstrate that clonal and nonclonal mutations arise within non-Ig AID target genes in the combined absence of UNG and MSH2 and that DNA strand lesions arise in an UNG-dependent manner but are offset by MSH2. These findings lend insight into a complex interplay whereby potentially deleterious UNG activity and general genomic instability are opposed by the protective influence of MSH2, producing a net protective effect that promotes immune diversification while simultaneously attenuating malignant transformation of GC B cells.
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PMID:AID-associated DNA repair pathways regulate malignant transformation in a murine model of BCL6-driven diffuse large B-cell lymphoma. 2638 50

Bovine leukemia virus (BLV) causes enzootic bovine leukosis, a malignant form of B-cell lymphoma, and is closely related to human T-cell leukemia viruses. We investigated whether BLV infection affects host genes associated with DNA mismatch repair (MMR). Next-generation sequencing of blood samples from five calves experimentally infected with BLV revealed the highest expression levels of seven MMR genes (EXO1, UNG, PCNA, MSH2, MSH3, MSH6, and PMS2) at the point of peak proviral loads (PVLs). Furthermore, MMR gene expression was only upregulated in cattle with higher PVLs. In particular, the expression levels of MSH2, MSH3, and UNG positively correlated with PVL in vivo. The expression levels of all seven MMR genes in pig kidney-15 cells and the levels of PMS2 and EXO1 in HeLa cells also increased tendencies after transient transfection with a BLV infectious clone. Moreover, MMR gene expression levels were significantly higher in BLV-expressing cell lines compared with those in the respective parental cell lines. Expression levels of MSH2 and EXO1 in BLV-infected cattle with lymphoma were significantly lower and higher, respectively, compared with those in infected cattle in vivo. These results reveal that BLV infection affects MMR gene expression, offering new candidate markers for lymphoma diagnosis.
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PMID:Bovine Leukemia Virus Infection Affects Host Gene Expression Associated with DNA Mismatch Repair. 3314 51