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At least 217 records · Page 12Linked to original sources
PubMed2002

VH gene analysis in sporadic Burkitt's lymphoma: somatic mutation and intraclonal diversity with special reference to the tumor cells involving germinal center.

We analyzed the immunoglobulin heavy chain variable region (V(H)) gene in seven cases of sporadic Burkitt's lymphoma (sBL) to elucidate their cell of origin. In particular, we focused on the V(H) gene status of tumor cells involving adjacent germinal center (GC) by microdissecting histological sections. Among the seven V(H) genes V(H)1 family was found in two, V(H)3 in four, and V(H)4 in one. All rearranged V(H) genes demonstrated somatic mutations at percentages ranging from 1.4 to 7.5% (mean, 4.2%), which is a similar level to that seen in IgM-only B cells. Three out of four V(H) genes with more than 2% sequence difference from their corresponding germline counterpart showed evidence of antigen selection in their framework region 3. Three cases demonstrated signs of intraclonal diversity with a mutational frequency of 0.47-0.98%, which was 13.5-28.8 times as great as the Taq infidelity in our experimental conditions. However the level of somatic mutation and the effect of antigen selection on V(H) gene were diverse in these three cases, and the relationship between V(H) gene somatic mutation status and intraclonal diversity was unclear in sBL. In the analysis of microdissected tissues, all 20 tumor clones in the adjacent GCs showed additional replacement mutations in complementarity determining region 3, suggesting a role of antigen in tumor progression. This finding resembles the phenomenon that memory B-cells reenter into GC to undergo further affinity maturation. In contrast, 7/11 V(H) gene sequences irrelevant to GC were identical to those of the major tumor clone. Thus our findings suggested that sBL is derived from memory B-cells rather than GC B-cells, and that antigen stimulation is involved in the clonal expansion of a proportion of sBL.

Amino Acid Sequence↗
PubMed1991

Genotoxicity evaluation of five tricyclic antidepressants in the wing somatic mutation and recombination test in Drosophila melanogaster.

Five tricyclic antidepressants were tested for genotoxicity using the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. Three-day-old larvae trans-heterozygous for 2 linked recessive wing hair mutants (multiple wing hairs and flare) were fed the test compounds in water mixed with a standard dry food for 48 h. Wings of the emerging adult flies were scored for the presence of spots of mutant cells which can be the consequence of either somatic mutation or mitotic recombination. Desipramine and imipramine were clearly genotoxic at concentrations above 1 mM whereas amitriptyline, nortriptyline and protriptyline were not genotoxic at concentrations up to 100 mM. This seems to implicate the nitrogen atom at position 5 in the 7-membered ring of the tricyclic molecule as being responsible for the genotoxic property of the compounds in Drosophila.

Amitriptyline↗
PubMed2005

EGFR mRNA is upregulated, but somatic mutations of the gene are hardly found in renal cell carcinoma in Japanese patients.

PURPOSE: Heterozygous somatic mutations of epidermal growth factor receptor (EGFR) in exons 18, 19, and 21 were recently reported to be associated with response to gefitinib in patients having nonsmall cell lung cancer. Such mutations are more frequently found among Japanese than Europeans. In this work, the frequency of mutations was investigated in renal cell carcinoma (RCC) samples obtained from Japanese subjects to examine the potential of gefitinib as a therapeutic agent for RCC. METHODS: Nineteen patients with RCC, who gave written informed consent, were enrolled in this study. mRNA expression levels of EGFR were measured in RCC and its adjacent noncancerous renal tissue via the real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. Somatic mutations were determined using genomic DNA extracted from RCC by direct sequencing method. RESULTS: mRNA expression was confirmed to be about 19 times higher in RCC than in adjacent noncancerous renal tissues, but no such mutations were detected in both. CONCLUSION: Results from this study do not support the validity of further clinical trials on gefitinib for RCC with genotyping even in Japanese patients, although EGFR plays a key role in tumor progression.

Carcinoma, Renal Cell↗
PubMed2000

Lack of CD95/FAS gene somatic mutations in extranodal, nodal and splenic marginal zone B cell lymphomas.

Germline CD95 (also known as FAS, APT1 and APO1) gene mutations have been associated with benign lymphoproliferative diseases and autoimmune processes. Somatic mutations have been reported in human tumours, including lymphomas. Since marginal zone B cell lymphomas usually arise in a background of chronic inflammation, often of autoimmune origin, we searched for CD95 gene mutations in an unselected series of marginal zone B cell lymphomas. The CD95/FAS full coding region, comprising exon-intron junctions, was amplified from genomic DNA by polymerase chain reaction (PCR) in 10 separate reactions. PCR products were analysed by single-strand conformation polymorphism (SSCP) and visualised by silver staining. Bands exhibiting an altered electrophoretic mobility were sequenced. Twenty-seven cases of marginal zone B cell lymphomas of whom fresh or frozen tumour material was available (18 extranodal, five splenic and four nodal) were studied. Previously described silent polymorphisms in exons 7 (C836T) and 3 (T416C) were detected in 42% and in 19% of the cases, respectively. One silent T-to-A substitution at bp 431, within exon 3, was found in one case. Our results did not reveal the presence of CD95 somatic mutations in unselected cases of marginal zone B cell lymphomas. On the basis of our data, we cannot rule out that other genes coding for proteins involved in the CD95-induced apoptotic pathway might be altered. However, this pathway does not seem to play an important role in the pathogenesis of these lymphoma subtypes.

Antigens, Neoplasm↗
PubMed1994

Germ-line and somatic mutations of the APC gene in patients with Turcot syndrome and analysis of APC mutations in brain tumors.

The Turcot syndrome (TS) is a rare, probably autosomal recessive, disorder characterized by development of primary neuroepithelial tumors of the central nervous system (CNS) and numerous adenomatous colorectal polyps. To examine the possible involvement of mutations of the APC gene, which is responsible for familial adenomatous polyposis (FAP), in Turcot syndrome, we examined DNAs from TS patients for alterations in this gene by means of ribonuclease protection analysis. Germ-line APC mutations were detected in each of three unrelated cases of TS, and additional (somatic) mutations were observed in colonic adenomas that had developed in one of these patients. However, no somatic mutations in APC were found among 91 neuroepithelial tumors (medulloblastoma, glioblastoma, astrocytoma, and oligodendroglioma), whether sporadic or associated with TS. These results suggest that the APC gene is associated with pathogenesis of one feature of TS, but that at least one other gene is responsible for the genesis of neuroepithelial tumors in the CNS.

Adenomatous Polyposis Coli↗
PubMed1999

Somatic mutations at the T-cell antigen receptor in antineoplastic drug-exposed populations: comparison with sister chromatid exchange frequency.

OBJECTIVE: The objective of this study was to assess the genetic effect of occupational exposure to antineoplastic agents. METHOD: The influence of occupational handling of cytotoxic drugs was investigated by monitoring the frequency of sister chromatid exchanges (SCE), the percentage of cells with high frequencies of SCE (high-frequency cells, HFC), and the frequency of somatic mutation at the T-cell receptor (TCR) locus in mononuclear cells of exposed hospital nurses. These parameters were also measured in healthy donors and in cancer patients at the time of the diagnosis and following the administration of high doses of cytotoxic drugs requiring stem cell support. RESULTS: Our results show that (a) SCE and HFC values in occupationally exposed nurses do not differ from controls, (b) patients with newly diagnosed cancer or following chemotherapy show a number of SCE comparable to those of healthy donors, but a significantly different percentage of HFC, (c) cigarette smokers of all categories studied show higher frequencies of SCE and HFC as compared to nonsmokers, but the differences are not statistically significant, (d) the mutation frequency at the TCR locus in oncology nurses is higher, but not significantly different from the frequency in the control group, and (e) the increase of mutation frequency is statistically significant and seems to be dose dependent in patients treated with high-dose chemotherapy. CONCLUSIONS: Our data suggest that SCE frequency and HFC percentage are not reliable indicators of exposure to possible mutagenic/carcinogenic effects of antineoplastic drugs; on the contrary, our observations indicate that anticancer therapy induces somatic mutations at the TCR locus and suggest an association between exposure to cytotoxic agents and the increase in somatic mutations.

Adult↗
PubMed1999

Rheumatoid factor isotype switch and somatic mutation variants within rheumatoid arthritis synovium.

The presence of clonally-related B-lymphocyte aggregates within synovial lining tisue of rheumatoid arthritis (RA) patients suggests a germinal centre-like reaction, which may hold implications for disease pathogenesis and the causes of chronic inflammation. We studied 250 rheumatoid factor (RF) heavy-chain sequences cloned from the synovium of three patients with RA, to determine whether they undergo both somatic mutation and isotype switching consistent with this hypothesis. Size analysis of immunoglobulin heavy-chain cDNAs from synovial RF+ B cells revealed oligoclonal RF+ populations and identically-sized VH-D-JH transcripts of different immunoglobulin isotypes. Sequencing of individual inserts selected from cloned immunoglobulin heavy-chain cDNAs demonstrated a clonal relationship between immunoglobulin M (IgM) RF and IgA RF, suggesting that this isotype switch occurred in synovium. Furthermore, most somatic mutations were found to have occurred after this isotype switch. This finding suggests that the RA synovial microenvironment sustains somatic mutation and isotype switching in RF-specific B lymphocytes akin to secondary lymphoid organs.

Aged↗
PubMed1993

Human IgM+IgD+ B cells, the major B cell subset in the peripheral blood, express V kappa genes with no or little somatic mutation throughout life.

Peripheral blood B cells of a 67-year-old person were separated into IgM+IgD+, IgM+IgD-, and IgM-IgD- subsets, and nucleotide sequences of expressed immunoglobulin light chain variable (V) regions encoded by V kappa 3 and V kappa 4 gene family members were determined from amplified cDNA. V region sequences from IgM+IgD+ cells (the major B cell population in the blood) showed no or little somatic mutation (0.3%), in contrast to V kappa sequences from IgM+IgD- and IgM-IgD- B cells (2.0% and 3.9%, respectively). This suggests that in the human like in the mouse, and independently of age, somatically mutated memory B cells accumulate in the compartment of IgM-IgD- cells, whereas the IgM+IgD+ subpopulation consists of cells whose antibody repertoire is mainly determined by V region gene rearrangements and N-region insertion, at the molecular level. The somatically mutated IgM+IgD- cells may represent early descendants of IgM+IgD+ cells recruited into the memory cell compartment.

Aged↗
PubMed1994

Analysis of individual immunoglobulin lambda light chain genes amplified from single cells is inconsistent with variable region gene conversion in germinal-center B cell somatic mutation.

Responding B cells in specific immune responses diversify their immunoglobulin genes and are selected on their variant antigen receptors in the microenvironment of the germinal center. The patterns of mutations previously reported for immunglobulin (Ig) genes have supported mechanistic hypotheses of either error-prone DNA synthesis or templated variable region gene conversion as the underlying mechanism in the generation of these mutations. To assess the role of gene conversion in germinal-center somatic mutation, we chose to examine nucleotide changes in mouse lambda light chain genes which arose in response to a specific antigen. Laboratory mice possess three V lambda subexons, two of which differ from one another by only seven nucleotides, making these two subexons ideal for gene conversion. In the current study, we used six-parameter flow cytometry to isolate single lambda light chain-expressing germinal-center B cells from two different time points in a primary immune response. We then individually amplified and sequenced individual V lambda 1 genes from these single cells for mutational analysis. None of the 32 V lambda 1 genes, containing a total of 40 mutations, showed evidence of gene conversion from either of the other V lambda subexons. Features such as the replacement to silent ratio of the mutations documented at the earlier time point indicate an absence of antigen-driven selection. These data indicate that V region gene conversion does not contribute to germinal-center somatic mutation and that gene conversion is not responsible for targeting mutation specifically to rearranged Ig genes. The biological implications are discussed.

Amino Acid Sequence↗
PubMed2026

Somatic mutations reveal hyperactive Notch signaling in prurigo nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by pruritic skin nodules of unknown etiology. Little is known about genetic changes in PN pathogenesis, particularly somatic events, which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 patients with PN and 10 patients with atopic dermatitis (AD) for comparison. Somatic mutational analysis revealed that PN lesional skin harbors recurrent somatic mutations in fibrotic, neurotropic, and cancer-associated genes that are absent in adjacent PN nonlesional skin. Nonsynonymous mutations were most frequently present in NOTCH1 and the Notch signaling pathway, a key regulator of cellular proliferation and tissue fibrosis. In contrast, NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, identified recurrently deleted and downregulated genes in PN lesional skin, which are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, a multicenter analysis revealed increased risk of NOTCH1-associated diseases in patients with PN. In characterizing the somatic landscape of PN, this study highlights the potential role of Notch pathway dysregulation in PN pathogenesis and fibrosis.

Humans↗
PubMed1981

Somatic mutation of immunoglobulin light-chain variable-region genes.

A single germline immunoglobulin kappa-variable-region gene, VK167, is rearranged and expressed in two myelomas, MOPC167 and MOPC511. Only this single germline gene displays close homology to the expressed genes. Neither of the rearranged, functional genes, however, has a nucleotide sequence that is identical to the germline VK167 gene. Both active genes display several single-base-pair mutations with respect to the germline sequence. The nucleotide sequence data predict the alteration of a restriction-enzyme-recognition site within the VK167 gene between germline cells and cells producing the MOPC167 light-chain protein. Based on this restriction-site alteration, Southern blot analysis proves unambiguously that no gene present in the germline BALB/c mouse genome contains the exact VK167 nucleotide sequence found in cells committed to MOPC167 antibody production. Instead the alterations found in the expressed MOPC167 and MOPC511 V-region genes have apparently arisen by a process of somatic mutation during cellular differentiation. Since nucleotide alterations are found in framework and hypervariable portions of the variable region, the mechanism of somatic mutation is not limited to hypervariable sequences. In addition, Southern blot hybridization indicates that the observed mutations did not arise by recombinational events, but are single-base-pair substitutions. Based on the distribution of mutations that have been found in expressed immunoglobulin variable-region genes, a model that links the introduction of somatic mutations to DNA replication during the V-J joining event is proposed.

Amino Acid Sequence↗
PubMed2004

Somatic mutations and altered expression of the candidate tumor suppressors CSNK1 epsilon, DLG1, and EDD/hHYD in mammary ductal carcinoma.

We report somatic mutations in three genes (CSNK1 epsilon, encoding the Ser/Thr kinase casein kinase I epsilon; DLG1, encoding a membrane-associated putative scaffolding protein; and EDD/hHYD, encoding a progestin induced putative ubiquitin-protein ligase) in mammary ductal carcinoma. These genes were suspected of playing a role in cancer because loss-of-function mutations in their Drosophila homologues cause excess tissue growth. Using DNA from 82 laser-microdissected tumor samples, followed by microsatellite analysis, denaturing HPLC and direct sequencing, we found multiple somatic point mutations in all three genes, and these mutations showed significant association with loss of heterozygosity of closely linked polymorphic microsatellite markers. For CSNK1 epsilon and DLG1, most of the mutations affected highly conserved residues, some were found repetitively in different patients, and no synonymous mutations were found, indicating that the observed mutations were selected in tumors and may be functionally significant. Immunohistochemical reactivity of each protein was reduced in poorly differentiated tumors, and there was a positive association between altered protein reactivity, loss of heterozygosity, and somatic mutations. There was a statistically significant association of hDlg staining with p53 and Ki67 reactivity, whereas CSK1 epsilon and EDD/hHYD staining levels were associated with progesterone receptor status. The results provide strong indications for a role of all three genes in mammary ductal carcinoma. They also justify additional studies of the functional significance of the changes, as well as a search for additional changes in these and other genes identified from studies on model systems.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Somatic mutations of the MTS (multiple tumor suppressor) 1/CDK4l (cyclin-dependent kinase-4 inhibitor) gene in human primary non-small cell lung carcinomas.

Cytogenetic abnormalities of chromosome 9p21-22 have been documented in human non-small cell lung carcinomas (NSCLC). Recently, a candidate tumor suppressor gene, MTS1/CDK4l, was identified in this chromosomal region and frequent homozygous deletions of this gene were found in cancer cell lines derived from various types of tissues. We screened 64 primary NSCLCs, including 31 adenocarcinomas and 33 squamous cell carcinomas, for mutations in MTS1/CDK4l, and detected somatic mutations in 19 of the 64 tumors examined. Five were deletions and 14 were missense mutations. These results suggest that inactivation of MTS1/CDK4l plays an important role during carcinogenesis of NSCLC.

Adenocarcinoma↗
PubMed2000

Somatic mutations and aging: a re-evaluation.

Aging has been explained in terms of an accumulation of mutations in the genome of somatic cells, leading to tissue atrophy and neoplasms, as well as increased loss of function. Recent advances in transgenic mouse modeling and genomics technology have created, for the first time, the opportunity to begin testing this theory. In this paper the existing evidence for a possible role of somatic mutation accumulation in aging will be re-evaluated on the basis of the evolutionary logic of aging and recent insights in genome structure and function. New strategies for investigating the relationship between genome instability, mutation accumulation and aging will be discussed.

Aging↗
PubMed2003

Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.

We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.

Animals↗
PubMed2000

Inactivation of germline mutant APC alleles by attenuated somatic mutations: a molecular genetic mechanism for attenuated familial adenomatous polyposis.

Germline mutations of the adenomatous polyposis coli (APC) tumor-suppressor gene result in familial adenomatous polyposis (FAP). Patients with FAP typically develop hundreds to thousands of benign colorectal tumors and early-onset colorectal cancer. A subset of germline APC mutations results in an attenuated FAP (AFAP) phenotype, in which patients develop fewer tumors and develop them at an older age. Although a genotype-phenotype correlation between the locations of APC germline mutations and the development of AFAP has been well documented, the mechanism for AFAP has not been well defined. We investigated the mechanism for AFAP in patients carrying a mutant APC allele (APC(AS9)) that has a mutation in the alternatively spliced region of exon 9. APC(AS9) was found to down-regulate beta-catenin-regulated transcription, the major tumor-suppressor function of APC, as did the wild-type APC. Mutation analysis showed that both APC(AS9) and the wild-type APC alleles were somatically mutated in most colorectal tumors from these patients. Functional analysis showed that 4666insA, a common somatic mutation in APC(AS9) in these tumors, did not inactivate the wild-type APC. Our results indicate that carriers of APC(AS9) develop fewer colorectal tumors than do typical patients with FAP because somatic inactivation of both APC alleles is necessary for colorectal tumorigenesis. However, these patients develop colorectal tumors more frequently than does the general population because APC(AS9) is inactivated by mutations that do not inactivate the wild-type APC.

Adenomatous Polyposis Coli↗
PubMed1994

Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma.

Loss of heterozygosity (LOH) studies have suggested that somatic mutations of a tumour suppressor gene or genes on chromosome 3p are a critical event in the pathogenesis of non-familial renal cell carcinoma (RCC). Germline mutations of the von Hippel-Lindau (VHL) disease gene predispose to early onset and multifocal clear cell renal cell carcinoma, and the mechanism of tumorigenesis in VHL disease is consistent with a one-hit mutation model. To investigate the role of somatic VHL gene mutations in non-familial RCC, we analysed 99 primary RCC for VHL gene mutations by SSCP and heteroduplex analysis. Somatic VHL gene mutations were identified in 30 of 65 (46%) sporadic RCC with chromosome 3p allele loss and one of 34 (3%) tumours with no LOH for chromosome 3p. The VHL gene mutations were heterogeneous (17 frameshift deletions, eight missense mutations, four frameshift insertions, one nonsense and one splice site mutation), but no mutations were detected in the first 120 codons of cloned coding sequence. Most RCCs with somatic VHL mutations (23 of 27 (85%) informative cases) had chromosome 3p25 allele loss in the region of the VHL gene so that both alleles of the VHL gene had been inactivated as expected from a two-hit model of tumorigenesis. Detailed histopathology was available for 59 of the tumours investigated: 18 of 43 (42%) RCC with a clear cell appearance had a somatic VHL gene mutation but none of 16 non-clear cell RCC (eight chromophilic, three chromophobe and five oncocytoma) (chi2 = 7.77, P < 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma, Clear Cell↗