Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Somatic mutation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 379 records · Page 21Linked to original sources
PubMed1987

Cloned mouse lymphocytes permit analysis of somatic mutations that occur in vivo.

As part of our mouse model of somatic mutation, we have begun to characterize spontaneously occurring hypoxanthine phosphoribosyltransferase (HPRT) -deficient mouse lymphocytes. Lymphocytes were cloned by in vitro exposure of spleen cells from male C57B1/6 mice to the mitogen concanavalin A, conditioned medium containing lymphocyte growth factors, and thioguanine (TG), in a limiting dilution assay. The 17 TG-resistant clones recovered were all highly deficient in HPRT activity and were found by analysis of surface antigens to be representative of the major subclasses of T lymphocytes. Southern analysis of lymphocyte genomic DNA detected alterations of the hprt gene in 12/17 of the HPRT-deficient lymphocyte clones. Of these 12, 2/17 were lacking the entire hprt locus, 7/17 lacked part of the locus, and 3/17 had other, unidentified alterations.

Animals↗
PubMed1990

Analysis of somatic mutations in kappa transgenes.

We have examined the nature and localization of somatic mutations in three kappa transgenes cloned from IgG-secreting hybridomas. All of the mutations identified were single base substitutions. Mutations were localized to the variable (V) region and its flanking sequences. In every case, the nuclear matrix association region, kappa enhancer, and C gene were spared. These data indicate that the rearranged kappa gene contains the necessary sequences for targeting of the mutation process, and suggest that the observed localization of mutations to the V region reflects the inherent specificity of this mutation process.

Animals↗
PubMed1996

Somatic mutation detection in human biomonitoring.

Somatic cell gene mutation arising in vivo may be considered to be a biomarker for genotoxicity. Assays detecting mutations of the haemoglobin and glycophorin A genes in red blood cells and of the hypoxanthine-guanine phosphoribosyltransferase and human leucocyte antigenes in T-lymphocytes are available in humans. This MiniReview describes these assays and their application to studies of individuals exposed to genotoxic agents. Moreover, with the implementation of techniques of molecular biology mutation spectra can now be defined in addition to the quantitation of in vivo mutant frequencies. We describe current screening methods for unknown mutations, including the denaturing gradient gel electrophoresis, single strand conformation polymorphism analysis, heteroduplex analysis, chemical modification techniques and enzymatic cleavage methods. The advantage of mutation detection as a biomarker is that it integrates exposure and sensitivity in one measurement. With the analysis of mutation spectra it may thus be possible to identify the causative genotoxic agent.

Environmental Monitoring↗
PubMed1997

Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281-->isoleucine) in the extracellular domain of the thyrotropin receptor.

Activating somatic mutations in the thyrotropin (TSH) receptor have been identified as a cause of hyperfunctioning thyroid adenomas, and germline mutations have been found in familial nonautoimmune hyperthyroidism and sporadic congenital hyperthyroidism. All mutations reported to date have been located in the transmembrane domain. We now report an example of an activating mutation in the extracellular, TSH-binding domain, found in a male infant with congenital hyperthyroidism due to a toxic adenoma. The pregnancy was remarkable for fetal tachycardia. Scintigraphic studies demonstrated a large nodule in the right lobe, and a hemithyroidectomy was performed at the age of 2 yr. Direct sequencing of the TSH receptor gene revealed a mutation in one allele resulting in a substitution of serine281 by isoleucine (Ser281--> Ile) in the extracellular domain. The mutation was restricted to the adenomatous tissue. Expression of the Ser281--> Ile mutation in vitro revealed an increase in basal cAMP levels. Affinity for TSH was increased by the mutation. These findings demonstrate that activating mutations can also occur in the extracellular domain of the TSH receptor, and support a model in which the extracellular domain serves to restrain receptor function in the absence of TSH or antibody-induced conformational changes.

Adenoma↗
PubMed1998

Truncating somatic mutation in exon 15 of the APC gene is a rare event in human breast carcinomas. Mutations in brief no. 179. Online.

Inactivation of the adenomatous polyposis coli (APC) gene is an early event in sporadic colorectal cancer. Somatic mutations have also been detected in cancers of the stomach, pancreas, thyroid, ovary and breast. Over 95% of the mutations reported in the APC gene are frameshift and nonsense mutations. The large exon 15 accounts for 77% of the coding sequence. The APC gene product interacts with cytoplasmic beta-catenin, mediates its degradation and thereby downregulates transcription exerted by the beta-catenin-Tcf complex. In the absence of a functional APC protein, beta-catenin is stabilized and accumulates in the cytoplasm. This results in uncontrolled transcriptional activation of Tcf responsive genes which may contribute to cancer progression. In order to investigate whether this pathway is disrupted by APC mutations in breast carcinoma cells, we screened 227 breast tumors for truncating mutations in exon 15 using the protein truncation test (PTT). Only one mutation, 4678delA, which was shown to be somatic, was detected by this approach. The mutation resided just outside the mutation cluster region (MCR) and resulted in a premature stop in codon 1564. Our findings do not indicate that the suppressive function of APC is commonly abrogated by truncating mutations in human breast carcinomas.

Alternative Splicing↗
PubMed1998

Erythrocyte as a potential model for study of lifelong somatic mutations.

The detection and measurement of somatic cell mutation in vivo is an important subject of research for the assessment of human cancer risk induced by various environmental genotoxic factors. The possible mechanisms which influence the persistence of mutant cells of the hematoimmune system in the peripheral blood are presented. The erythroid system is a system which accumulates mutational lesions and so stably generates red blood cells with various phenotypic changes.

Environmental Pollution↗
PubMed1994

Frequent somatic mutation of the MTS1/CDK4I (multiple tumor suppressor/cyclin-dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma.

We previously reported frequent loss of heterozygosity on chromosome 9p in esophageal carcinomas and suggested that a tumor suppressor gene located on this chromosomal arm might be involved in development of these cancers. Since recently published studies have shown that a gene mapped on chromosome 9p21, MTS1/CDK4I (multiple tumor suppressor 1/cyclin-dependent kinase 4 inhibitor), is frequently mutated in various types of tumors, we chose to examine esophageal squamous cell carcinomas for mutations in this candidate gene. DNA sequence analyses revealed somatic mutations of MTS1/CDK4I in 14 of 27 tumors examined; 8 were frame-shift mutations and 6 were missense mutations. These results suggested that the MTS1/CDK4I gene is a tumor suppressor the inactivation of which plays an important role during carcinogenesis of the squamous cell type of esophageal carcinoma.

Base Sequence↗
PubMed1989

Early onset of somatic mutation in immunoglobulin VH genes during the primary immune response.

The dynamics of somatic mutation in Ig variable genes was investigated in order to define a population of B cells undergoing mutation. BALB/cJ mice were injected with PC-KLH, and splenic RNA was prepared 5, 7, and 13 d later. The mRNA was annealed to gamma constant region primers to make cDNA transcripts encoding VH genes. 103 cDNA clones corresponding to 18 different genes from the VH7183, VH3660, and VHS107 subfamilies were sequenced to identify mutation. VH genes had a low level of mutation on day 5 after immunization and accumulated more mutation by day 7 at a rate of 10(-3) mutations per nucleotide per generation. However, by day 13, the number of mutations per gene did not increase, and most of the substitutions encoded replacement amino acid changes that were clustered in the hypervariable regions, indicating that the mutational process was less active during the second week and that antigen selection had occurred. The data are consistent with a developmentally regulated mechanism in which mutation is activated during the first week of the primary immune response for a limited time period, after which selection acts to preserve the beneficial mutants.

Animals↗
PubMed2006

Lack of somatic mutations in EGFR tyrosine kinase domain in hepatocellular and nasopharyngeal carcinoma.

Activating EGFR somatic mutations have been shown to predict treatment response to small molecules targeting the EGFR intracellular tyrosine kinase domain. Recent work on cell-lines and animal models had demonstrated an inhibitory effect of EGFR tyrosine kinase inhibitors in hepatocellular and nasopharyngeal carcinoma, and clinical trials in these tumour types are ongoing. There are few data on the presence or prevalence of EGFR mutations in hepatocellular and nasopharyngeal carcinomas. We studied exons 18-21 of the EGFR gene from 100 hepatocellular and 102 nasopharyngeal carcinomas, and found no exonic mutations of potential significance. Alternative mechanisms may be important for the observed activity of small molecule EGFR tyrosine kinase inhibitors in hepatocellular and nasopharyngeal carcinomas.

Carcinoma, Hepatocellular↗
PubMed2006

Statistical analysis of pathogenicity of somatic mutations in cancer.

Recent large-scale sequencing studies have revealed that cancer genomes contain variable numbers of somatic point mutations distributed across many genes. These somatic mutations most likely include passenger mutations that are not cancer causing and pathogenic driver mutations in cancer genes. Establishing a significant presence of driver mutations in such data sets is of biological interest. Whereas current techniques from phylogeny are applicable to large data sets composed of singly mutated samples, recently exemplified with a p53 mutation database, methods for smaller data sets containing individual samples with multiple mutations need to be developed. By constructing distinct models of both the mutation process and selection pressure upon the cancer samples, exact statistical tests to examine this problem are devised. Tests to examine the significance of selection toward missense, nonsense, and splice site mutations are derived, along with tests assessing variation in selection between functional domains. Maximum-likelihood methods facilitate parameter estimation, including levels of selection pressure and minimum numbers of pathogenic mutations. These methods are illustrated with 25 breast cancers screened across the coding sequences of 518 kinase genes, revealing 90 base substitutions in 71 genes. Significant selection pressure upon truncating mutations was established. Furthermore, an estimated minimum of 29.8 mutations were pathogenic.

Amino Acid Sequence↗
PubMed1990

On the use of excision repair defective cells in the wing somatic mutation and recombination test in Drosophila melanogaster.

Ten chemical mutagens were tested in the wing somatic mutation and recombination test in Drosophila melanogaster. This assay makes use of genetic markers expressed on the wing of adult flies. Larvae which are trans-heterozygous for mwh (multiple wing hairs) and flr (flare) were fed with the compounds either acutely (2, 4, or 6 hr) or chronically (48 or 72 hr), or were treated by inhalation (1 hr). Genetic changes induced in the somatic cells of the wing imaginal discs lead to the formation of mutant clones on the wing (mwh and/or flr). Single spots are produced by point mutation, chromosome breakage, and mitotic recombination; twin spots are produced exclusively by mitotic recombination. All 10 mutagens belonging to different chemical classes were clearly positive in this assay. However, the choice of the optimal treatment conditions (concentration of compound, duration of treatment, age of larvae at treatment) is essential. Eight of the compounds were also tested in excision repair defective cells by introducing the mei-9L1 mutation into the test system. This seems not to improve the detection capacity of the assay, mainly because only small spots are found in excision repair defective wings. In addition, the frequencies of spots in these wings are enhanced four to five times, which makes the scoring more tedious. For these and other practical reasons the use of this specific cross is not recommended in the wing spot test for routine screening purposes.

Animals↗
PubMed1995

Somatic mutation favors the evolution of diploidy.

Explanation of diploidy have focused on advantages gained from masking deleterious mutations that are inherited. Recent theory has shown that these explanations are flawed. Indeed, we still lack any satisfactory explanation of diploidy in species that are asexual or that recombine only rarely. Here I consider a possibility first suggested by Efroimson in 1932, by Muller in 1964 and by Crow and Kimura in 1965: diploidy may provide protection against somatic, not inherited, mutations. I both compare the mean fitness of haploid and diploid populations that are asexual and investigate the invasion of "diploidy" alleles in sexual populations. When deleterious mutations are partially recessive and somatic mutation is sufficiently common, somatic mutation provides a clear advantage to diploidy in both asexual and sexual species.

Biological Evolution↗
PubMed1997

Somatic mutation of the tuberous sclerosis (Tsc2) tumor suppressor gene in chemically induced rat renal carcinoma cell.

PURPOSE: von Hippel-Lindau (VHL) gene mutations are detected in noninherited, sporadic human renal cell carcinomas (RCs) at a high frequency. We recently identified a germline mutation in the rat homologue of the human tuberous sclerosis (TSC2) predisposing RC gene in the Eker rat model, and in this study we searched for mutations of the Tsc2 gene in chemically induced non-Eker rat RCs. MATERIALS AND METHODS: Chemically [N-ethyl-N-hydroxyethylnitrosamine (EHEN)]-induced non-Eker rat RC lines (designated as BP13 and BP36B) were subjected to PCR-single strand conformation polymorphism (PCR-SSCP) analysis using specific primers covering entire exons of Tsc2 gene (41 coding exons and one non-coding exon). We simultaneously searched for mutations of Vhl gene, a rat homologue of von Hippel-Lindau disease gene (VHL) as well as Tsc2 gene. RESULTS: BP36B showed an abnormal mobility shift from the normal tissue of the same rat in exon 35 on analysis by PCR-SSCP. This mutation was confirmed by direct sequencing and found to be a T-to-C transition at the second position of codon 1470, resulting in an amino acid change from leucine to proline (missense mutation). CONCLUSIONS: This is the first demonstration of Tsc2 gene somatic mutation in non-Eker rat RCs. Our present findings call attention to further investigation of the role of Tsc2 gene mutations in rat renal carcinogenesis and possible Tsc2 gene mutations in human RCs, especially of the non-clear cell type, which are not related to the VHL gene.

Animals↗
PubMed1995

Infrequent somatic mutation of the MTS1 gene in primary bladder carcinomas.

We examined a candidate tumor suppressor gene on chromosome 9p21, MTS1/CDK4I (multiple tumor suppressor 1/cyclin-dependent kinase 4 inhibitor), which has been found to be mutated frequently in cell lines derived from bladder carcinomas, for somatic mutations in 39 primary bladder cancers by means of SSCP (single-stranded conformational polymorphism) and DNA sequencing. Mutations were detected in two of these carcinomas; one was a 61-base deletion and the other a 1-base deletion. In both cases the homologous allele was missing, indicating that "two-hit" mutation of the MTS1 gene had taken place in these tumors. The results indicated that inactivation of the MTS1 gene is likely to be a contributing factor in some, but not the majority of, bladder cancers.

Base Sequence↗
PubMed2006

Immunoglobulin genes in multiple myeloma: expressed and non-expressed repertoires, heavy and light chain pairings and somatic mutation patterns in a series of 101 cases.

BACKGROUND AND OBJECTIVES: The available data on the immunoglobulin gene (IG) repertoire in multiple myeloma (MM) derive mainly from heavy chains; considerably less is known about light chains. We assessed in parallel IGH and IGK/IGL rearrangements in 101 MM patients so as to gain insight into: (i) IG repertoires; (ii) antigen impact; (iii) the role of receptor editing. DESIGN AND METHODS: Bone marrow aspirates were collected from all cases. IGHV-(D)-J and IGLV-J rearrangements were amplified by reverse transcriptase polymerase chain reaction (PCR). In all cases, IGKV-J rearrangements were analyzed in parallel on cDNA/genomic DNA. IGKV-KDE and IGKJ-C-INTRON-KDE were also amplified by DNA-PCR. RT-PCR products were directly sequenced. RESULTS: IGHV3 genes predominated; the IGHV4-34 gene was used in only one case. Five IGKV and five IGLV genes accounted for the majority of in-frame, transcribed IGKV-J or IGLV-J rearrangements. Taking IGKV-J, IGKV-KDE and IGKJ-C-INTRON-KDE rearrangements together, biallelic IGK locus rearrangements were detected in 22/43 k-MM cases. In l-MM, 36/42 cases had at least one rearranged IGK allele; 8/19 IGKV-J rearrangements in l-MM were in-frame. All in-frame, transcribed IGH/IGK/IGL sequences were mutated; parallel heavy/light chain analysis demonstrated a comparable impact of somatic hypermutation. INTERPRETATION AND CONCLUSIONS: Biases in IG repertoire did not seem disease-related but followed a similar pattern to that of the normal repertoire. The under-representation of the IGHV4-34 gene provides an explanation for the paucity of autoimmune phenomena in MM. Somatic mutation patterns indicate the complementary role of MM IGH/IGK/IGL sequences in antigen recognition. Finally, the frequent inactivation of productive IGKV-J joints by secondary rearrangements in MM suggests active receptor editing.

Bone Marrow Cells↗
PubMed1996

The somatic white-ivory eye spot test does not detect the same spectrum of genotoxic events as the wing somatic mutation and recombination test in Drosophila melanogaster.

A groups of six chemical compounds was tested in parallel in two different somatic genotoxicity assays in Drosophila melanogaster, the wing somatic mutation and recombination test (SMART) and the white-ivory eye spot test. The wing spot test makes use of the wing cell markers multiple wing hairs (mwh) and flare (flr) and detects both mitotic recombination and various types of mutational events. The white-ivory eye spot test makes use of the white-ivory (wi) quadruplication and detects the somatic reversion of the recessive eye color mutation wi to the wild-type (w+). Three- or two-day-old larvae were fed chronically with the compounds ethylnitrosourea (ENU), N-nitrosopyrrolidine (NNP), caffeine (CAF), chromium (VI) oxide (CRO), potassium chromate (POC), and 2,4-dichlorophenoxyacetic acid (2,4-D). All six compounds are genotoxic to various degrees in the wing spot test. The percentage of the genotoxic activity that is due to mitotic recombination was between 84% and 91% for the hexavalent chromium compounds CRO and POC and about 68% for 2,4-D. In contrast, ENU and NNP showed only 46% and 25% recombinagenic activity, respectively. In the white-ivory eye spot test, the three compounds (CRO, POC, and 2,4-D) with high recombinagenic activity and CAF were clearly nongenotoxic, whereas only ENU and NNP gave a positive response. From these results, it is concluded that the spectrum of genotoxic events detected by the two assays is different. In particular, the white-ivory eye spot test appears not to detect mitotic recombination the way the wing spot test does.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2000

Somatic mutations in the STK11/LKB1 gene are uncommon in rare gynecological tumor types associated with Peutz-Jegher's syndrome.

Peutz-Jegher's syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyposis, and predisposition to benign and malignant tumors of the gastrointestinal tract, breast, ovary, uterine cervix, and testis. Germline-inactivating mutations in one allele of the STK11/LKB1 gene at chromosome 19p13.3 have been found in most PJS patients. Although ovarian sex cord tumors with annular tubules (SCTATs) and minimal deviation adenocarcinomas (MDAs) of the uterine cervix are very rare in the general population, both tumor types occur with increased frequency in women with PJS. An earlier report indicated that the 19p13.3 region containing the STK11 gene was affected by loss of heterozygosity (LOH) in nearly 50% of MDAs of the uterine cervix. We investigated the role of STK11 mutations and LOH of the 19p13.3 region in two PJS-associated SCTATs and in five SCTATs and eight MDAs of the uterine cervix, which occurred in patients lacking features of PJS (referred to here as "sporadic" cases). Germline mutations in the STK11 gene, accompanied by LOH of markers near the wild-type STK11 allele, were found in the two PJS-associated SCTATs. Somatic mutations in the coding region of STK11 were not found in any of the sporadic SCTATs or MDAs studied, although LOH of the 19p13.3 region was seen in three of eight MDAs. Our findings indicate that STK11, like other tumor suppressor genes, is affected by biallelic inactivation in gynecological tumors of PJS patients. In addition, although LOH of the 19p13.3 region was seen in sporadic MDAs, somatic STK11 mutations are rare. A yet-to-be-defined tumor suppressor gene in the 19p13.3 region may be the specific target of inactivation in these tumors.

AMP-Activated Protein Kinase Kinases↗
PubMed2006

Clinicoprognostical features of endometrial cancer patients with somatic mtDNA mutations.

Somatic mitochondrial DNA (mtDNA) mutations have been found in a subset of endometrial cancers (EC) from different populations. We have investigated the relationship between mtDNA changes and clinical and pathological variables of women affected by EC. mtDNA mutations were detected both in early (3/32; 9%) and in advanced (1/8; 12%) stages of uterine tumors. However, patients carrying the mtDNA mutations or the normal mtDNA sequence had indistinguishable clinicopathological data, including age, clinical stage, histological grade and type or depth of myometrial invasion. It is noteworthy that mtDNA mutations were not detected in hyperplastic endometrial tissues or in ECs coexisting with hyperplasia, nor in a single case of endometrial stromal sarcoma. LOH at the tumor suppressor genes RB1 and TP53 as well as p16INK4A alterations (LOH, gene deletion) were found in tumors carrying mtDNA mutations. These results suggest that somatic mtDNA mutations are detected in a subset of ECs, although they are unrelated to clinicopathological variables of cancer.

Adult↗