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 541 records · Page 30Linked to original sources
PubMedDate not supplied

Somatic mutations in the neurofibromatosis 1 gene in gliomas and primitive neuroectodermal tumours.

The increased frequency of glioma among neurofibromatosis 1 (NF1) patients suggests a general involvement of the NF1 gene in glioma tumourigenesis. Using the methodology of conventional Southern blotting with a complete panel of overlapping partial cDNAs covering the whole NF1 gene, we screened 31 gliomas of several different subtypes and 3 primitive neuroectodermal tumours (PNETs) from non-NF1 patients for aberrant restriction patterns in their tumour DNA samples. Clear evidence for somatic mutation events at the NF1 gene locus was found in 1 astrocytoma, 2 glioblastomas, 1 ependymoma and 1 PNET with an astrocytic component. These results suggest that the NF1 gene is important in suppressing tumours of neuroectodermal origin.

Aged↗
PubMed2006

Effect of different Thai traditional processing of various hot chili peppers on urethane-induced somatic mutation and recombination in Drosophila melanogaster: assessment of the role of glutathione transferase activity.

Four different Thai traditional chili peppers, namely bird pepper (Capsicum frutescens), red chili spur peppers (Capsicum annuum), green bell peppers and sweet pepper (C. annuum) were investigated for their antimutagenic properties. Each chili was prepared in three formulations commonly used for chili food processing; raw paste (chili ground in water), pickled in vinegar or stir-fried in palm oil. Each sample was tested for its antimutagenic effect against urethane by using the somatic mutation and recombination of wing hair of Drosophila melanogaster as an indicator. Three-day-old larvae, trans-heterozygous for two genetic markers, multiple wing hairs mwh and orrigon (ORR;flr3), were exposed to urethane alone or in combination with each chili formulation. The various processing methods for chilies differentially extracted the antimutagenic chili components. The specific chili as well as the method of processing influenced the observed antimutagenic properties against urethane. This suggested each chili contains a unique complex mixture of many antimutagens. Co-treatment and pre-treatment experiments showed that both direct and indirect protective mechanisms are involved in an 'activation' process to give antimutagenesis effects. An association between antigenotoxicity and glutathione transferase activity could not be established.

Animals↗
PubMed2005

Targeted somatic mutation of the BCL6 proto-oncogene and its impact on lymphomagenesis.

Cloning translocation breakpoints which cluster suspiciously to specific chromosomal loci has proved fruitful, leading to the identification of genes implicated in the onset of hematological malignancy. One of the most notable is BCL6, located on chromosome 3q27. The BCL6 is now known to encode a nuclear transcriptional repressor, with pivotal roles in germinal center (GC) formation and regulation of lymphocyte function, differentiation and survival. Unusually, the BCL6 gene locus is also actively targeted by the somatic mutation (SM) mechanism, at a rate indicative of specific, regulated events in both normal and malignant B-cells. These mutations occur in approximately 30% of normal centrocytes and centroblasts, but not in naive or pre-GC B-cells. They are also observed in approximately 70% of diffuse large B-cells lymphomas, approximately 30% of follicular lymphomas (FL) and at various frequencies in many lymphoma subtypes. Mutations are generated in the 5' proximity of the BCL6 promoter, including the first intron and are mainly single nucleotide substitutions, but with insertions and deletions also observed. Mutations in BCL6 occur independently of translocations, although mutational levels can be dramatically influenced by aberrantly translocated chromosomal elements, which map in the vicinity of the gene. Indeed, SMs are directly implicated in the generation of chromosomal translocations, as suggested by the overlap of the breakpoint cluster region and the mutational cluster domain. The prognostic value of the overall level of BCL6 mutations in specific lymphoma populations is, in the main, not as yet fully resolved. The accumulation of mutations in BCL6 during high grade transformation of FL, a mutational clustering and specific recurrent mutations suggest that some mutations may be selected for by their effect on the survival of the tumoral clone. In fact, it is now clear that SM can target and disrupt regulatory motifs in BCL6 to result in upregulated gene expression. Exogenous factors can also perturbate SM in BCL6. Viral infection elevates BCL6 mutational activity, suggesting a potential link with onset of virus-associated lymphoma. These findings to date reveal several mechanisms which can influence specific mutations targeting BCL6, and which may contribute to lymphomagenesis by dysregulating control of BCL6 expression.

Animals↗
PubMed2004

Somatic mutation of p53 leads to estrogen receptor alpha-positive and -negative mouse mammary tumors with high frequency of metastasis.

Approximately 70% of human breast cancers are estrogen receptor alpha (ERalpha)-positive, but the origins of ERalpha-positive and -negative tumors remain unclear. Hormonal regulation of mammary gland development in mice is similar to that in humans; however, most mouse models produce only ERalpha-negative tumors. In addition, these mouse tumors metastasize at a low rate relative to human breast tumors. We report here that somatic mutations of p53 in mouse mammary epithelial cells using the Cre/loxP system leads to ERalpha-positive and -negative tumors. p53 inactivation under a constitutive active WAPCre(c) in prepubertal/pubertal mice, but not under MMTVCre in adult mice, leads to the development of ERalpha-positive tumors, suggesting that target cells or developmental stages can determine ERalpha status in mammary tumors. Importantly, these tumors have a high rate of metastasis. An inverse relationship between the number of targeted cells and median tumor latency was also observed. Median tumor latency reaches a plateau when targeted cell numbers exceed 20%, implying the existence of saturation kinetics for breast carcinogenesis. Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors. Thus, this tumor system reproduces many important features of human breast cancer and provides tools for the study of the origins of ERalpha-positive and -negative breast tumors in mice.

Alleles↗
PubMed2001

Somatically mutated regions of immunoglobulin on human B-cell lymphomas code for peptides that bind to autologous major histocompatibility complex class I, providing a potential target for cytotoxic T cells.

Lymphoma-derived immunoglobulin idiotype (Id) is a well-characterized, tumor-specific antigen on B-cell malignancies. Immunotherapy using lymphoma immunoglobulin can lead to clinical responses mostly associated with anti-Id antibody. We cloned the Id from B-cell lymphomas, sequenced them, and used bioinformatics to select autologous MHC class I binding peptides from somatically mutated regions of the lymphoma Id. Peptides from patients who were HLA-A1, HLA-A2, HLA-A3, or HLA-A11 positive were analyzed in the T2 stabilization assay and a competitive peptide-binding assay. By both methods, approximately half of the peptides analyzed, regardless of HLA type, bound with intermediate or high affinity. Peptide binding affinity was similar to viral peptide sequences known to provide targets for cytotoxic T cells. Further investigation of lymphocyte responses to stimulation by autologous Id peptides versus Id peptides from other patients revealed that three of five patients in complete remission or with low volume, stable disease responded to self-peptides by IFN-gamma secretion greater than that seen with non-self peptides, whereas none of five patients with progressive disease responded to their own lymphoma Id. We have shown that mutated regions of lymphoma Id contain MHC class I binding peptides that are potential targets for cytotoxic T cells. Immunotherapy using the tumor-specific mutated regions from lymphoma Id avoids the need to break innate tolerance toward the germ-line protein sequences present on normal and malignant B cells.

Amino Acid Sequence↗
PubMed1995

Somatic mutations of the PIG-A gene found in Japanese patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematologic disorder caused by deficient biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. PIG-A, an X-linked gene that participates in the first step of GPI-anchor synthesis, is responsible for PNH. Abnormalities of the PIG-A gene have been demonstrated in all patients with PNH that have been studied to date. In this study, we analyzed 14 Japanese patients with PNH and identified 15 somatic mutations of PIG-A. The mutations included eight single-base changes and seven frame shift mutations. The single-base changes were two nonsense, three missense, and three splice site mutations. The frame shift mutations were four single-base deletions, two single-base insertions, and a replacement of two bases with one. They were all different, except for the same missense mutation being found in two patients. Moreover, these mutations were distributed in various regions of the gene. These results indicated that the mutations occurred at random sites and that there is no mutation hot spot in the PIG-A gene. All the mutations resulted in complete loss of function. Interestingly, the granulocytes in these patients contained variable proportions of mutant cells, suggesting that clonal expansion is not determined solely by mutations but is influenced by another factor(s).

Antigens, CD↗
PubMed1993

The human prohibitin (PHB) gene family and its somatic mutations in human tumors.

Five cosmid clones, isolated by procedures to screen genomic libraries for homologous variants of the human prohibitin gene (PHB), were analyzed to determine their genomic structures. Four of these (PHBP1-4) were found to be processed pseudogenes, each located on a different chromosome from their counterparts on chromosome 17q21. The DNA sequence of one clone (PHBP1, on chromosome 6q25) shared a 91.3% identity at the nucleotide level with the cDNA of functional prohibitin. A large number of human tumors of the breast, ovary, liver, and lung were examined for somatic mutations in the PHB gene. Although mutations were observed in a few sporadic breast cancers, none were identified in any of the other cancers.

Base Sequence↗
PubMed1995

Somatic mutations in the neurofibromatosis type 2 gene in sporadic meningiomas.

Meningiomas are benign tumors of the central nervous system. Although usually sporadic, they can occur in patients affected by the autosomal dominant syndrome, neurofibromatosis type 2 (NF2). The NF2 gene has recently been isolated from chromosome 22. The presence of germline mutations in NF2 patients and the loss of heterozygosity (LOH) on 22q in NF2 tumors support the hypothesis that the NF2 gene acts as a tumor suppressor. Cytogenetic and LOH studies have suggested that the gene responsible for the development of meningiomas is located in the region of 22q in which the NF2 gene maps. The meningiomas gene could therefore be the NF2 gene itself. Recently, somatic mutations of the NF2 gene have been identified in sporadic meningiomas, thus supporting the hypothesis that the NF2 gene is also important in meningioma pathogenesis. In this study, we analyzed sixty-one sporadic meningiomas for LOH of 22q and for mutations in the NF2 gene. LOH was detected in 36 of the 60 informative tumors. Single-strand conformational polymorphism analysis was used to identify nine mutations in five of the eight exons of the NF2 gene studied. The nine tumors with an altered NF2 gene also showed LOH for 22q markers. These results further support the hypothesis that mutations in the NF2 gene are a critical pathogenetic event in at least some meningiomas.

Aged↗
PubMedDate not supplied

The role of clonal selection and somatic mutation in autoimmunity.

Polyclonal activation has been proposed as the reason that autoantibodies are produced during autoimmune disease. This model denies a role for specific antigen selection of B cells and predicts instead a multiclonal population of unmutated or randomly mutated autoantibodies. We have found that the genetic features and clonal composition of spontaneously derived immunoglobulin G (IgG) antiself-IgG (rheumatoid factor (RF] autoantibodies derived from the autoimmune MRL/lpr mouse strain are inconsistent with both the predictions of this model and the actual outcome of experimental polyclonal activation. Instead we have found that MRL/lpr RFs are oligoclonal or even monoclonal in origin. They harbour numerous somatic mutations which are distributed in a way that suggests immunoglobulin-receptor-dependent selection of these mutations. In this sense, the MRL/lpr RFs resemble antibodies elicited by exogenous antigens after secondary immunization. The parallels suggest that, like secondary immune responses, antigen stimulation is important in the generation of MRL/lpr RFs.

Amino Acid Sequence↗
PubMed1999

Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in one of three genes: PKD1 on chromosome 16 accounts for approximately 85% of cases whereas PKD2 on chromosome 4 accounts for approximately 15%. Mutations in the PKD3 gene are rare. All patients present with similar clinical phenotypes, and the cardinal symptom is the formation of fluid-filled cysts in the kidneys. Previous work has provided data supporting the notion that cysts in ADPKD1 are focal in nature and form after loss of function of polycystin 1. This became evident by demonstrating that the normal PKD1 allele was inactivated somatically by loss of heterozygosity or by mutagenesis in a subset of renal or liver cysts examined. We show in this report, for the first time, multiple novel somatic mutations within the PKD2 gene of epithelial cells, in both kidneys of an ADPKD2 patient. From a total of 21 cysts examined, seven (33%) had the same C insertion within the inherited wild-type allele. In two other cysts, a nonsense mutation and a splice site AG deletion had occurred in a PKD2 allele that could not be identified as the inherited wild-type or mutant. We suggest that the autosomal dominant form of ADPKD2 occurs by a cellular recessive mechanism, supporting a two-hit model for cyst formation.

Aged↗
PubMed1997

Somatic mutations of the von Hippel-Lindau tumor suppressor gene and loss of heterozygosity on chromosome 3p in human glial tumors.

Molecular genetic analysis of von Hippel-Lindau tumor suppressor gene (VHL gene) was performed on 38 tissues of human glial tumors (ependymoma, 1; astrocytoma, 6; oligodendroglioma, 1; oligoastrocytoma, 2; anaplastic oligoastrocytoma, 3; anaplastic astrocytoma, 14; glioblastoma multiforme, 11). Somatic DNAs extracted from frozen tumor specimens were examined by single-strand conformational polymorphism analysis and direct sequencing. In addition, loss of heterozygosity (LOH) on chromosome 3p in 15 glial tumor cases, lymphocyte DNAs of which were available, was examined by use of 10 microsatellite probes and two polymorphism markers for the VHL gene. Two cases of low-grade gliomas showed somatic sense mutations in exon 3 of the VHL gene, and 6 of 15 cases (40.0%) showed LOH of chromosome 3p. The VHL gene-mutated cases also showed LOH. The retention of heterozygosity and high pathological grade of glial tumors were correlated significantly. In addition, Kaplan-Meier survival analysis for patients with glial tumors showed that patients with LOH had a significantly longer survival time than those without LOH. These results suggest that somatic mutations on 3p, including the VHL gene, may be involved in tumorigenesis of some low-grade glial tumors.

Adult↗
PubMed1993

Immunohistological evidence for second or somatic mutations as the underlying cause of dystrophin expression by isolated fibres in Xp21 muscular dystrophy of Duchenne-type severity.

Using five monoclonal antibodies against different parts of the dystrophin molecule, we have studied the dystrophin composition of 17 dystrophin-positive fibres in a muscle biopsy from a boy with Xp21 muscular dystrophy of Duchenne-type severity. The fibres showed five distinct, reproducible, immunoreactive dystrophin profiles. All the profiles included both the N-terminal and the C-terminal domains, but between these domains, different fibres were negative for different antibodies, suggesting the somatic loss of certain exons. We interpret this as the first in situ evidence of an individual having different patterns of missing exons leading to restoration of the reading frame in various ways in the original germline frame-shifting deletion of exons 35-43. It follows that various somatic mutations had taken place in different fibres.

Antibodies, Monoclonal↗
PubMed2006

Development of a mantle cell lymphoma in an ATM heterozygous woman after occupational exposure to ionising radiation and somatic mutation of the second allele.

Predisposition to lymphomagenesis is a well-known phenomenon of ataxia-telangiectasia, a recessive disorder caused by germline inactivation of ATM. ATM encodes a protein implicated in the repair of radiation induced double-strand breaks. Biallelic ATM inactivation was described also in sporadic lymphoid malignancies, supporting a role of ATM as a tumour suppressor gene. It is, however, still unclear whether ATM heterozygotes are at higher risk of tumours. We describe an ATM heterozygous patient, who developed a mantle cell lymphoma (MCL) after occupational exposure to ionising radiation and somatic mutation of the second ATM allele supporting the contention that heterozygous germline ATM alterations in combination with irradiation exposure predisposes to sporadic MCL.

Alleles↗
PubMed2002

Mitochondrial targeting of human 8-oxoguanine DNA glycosylase hOGG1 is impaired by a somatic mutation found in kidney cancer.

Oxidative damage to mitochondrial DNA (mtDNA) has been implicated as a contributing factor to the origin of many pathological processes. Among the major DNA lesions generated by oxidative stress, 8-oxoguanine (8-oxoG) has a strong mutagenic potential. The main pathway for the repair of this lesion is the base excision repair (BER) initiated by the OGG1 DNA glycosylase. In human cells alternative splicing of the hOGG1 transcript yields two forms of the protein, alpha and beta, that are localised in the nucleus and the mitochondria, respectively. We describe here a hOGG1 somatic mutation, found in a kidney cancer, that modifies the intracellular localisation of beta-hOGG1. The glycine 12 to glutamic acid substitution does not affect the enzymatic activity of the enzyme but lies in what was predicted to be a mitochondrial targeting sequence (MTS). Immunocytochemical localisation experiments show that the G12E mutant protein has diffuse cytoplasmic distribution instead of the mitochondrial localisation found for the wild-type, providing an example of a single amino acid substitution capable of disrupting a MTS. These results imply that these cancer cells are deficient in their mitochondrial 8-oxoG DNA repair activity.

Cell Nucleus↗
PubMed2004

[Frequent somatic mutations of the von Hippel-Lindau (VHL) tumor suppressor gene and its meaning in sporadic human renal clear cell carcinoma].

OBJECTIVE: To investigate the mutation of VHL gene, an important tumor suppressor gene in primary sporadic human renal cell carcinoma (RCC) and analyse its relationships with pathological stage and grade of renal cell carcinoma. METHODS: We analyzed 57 cases of primary sporadic Chinese renal clear carcinoma using the polymerase chain reaction (PCR) and denaturing high performance liquid chromatography(DHPLC). All positive cases in DHPLC analysis were further characterized by direct sequencing. RESULTS: Somatic mutations were detected in 30 (53%) of 57 clear cell renal carcinomas including 13 deletions, 2 insertions, and 15 missense mutations. These mutations mainly occurred in the last one-third region of exon 1, 2,and 3. CONCLUSION: VHL tumor suppressor gene is one of the major tumor suppressor genes in human renal cell carcinoma and there are frequent mutations of VHL in primary sporadic Chinese renal clear cell carcinomas. The mutations of VHL gene were irrespective of the age and pathological grade and stage of patients.

Adult↗
PubMed2005

A carcinogenic western diet does not induce somatic mutations in various target tissues of transgenic C56BL/6 mice.

Although the importance of diet in human cancer is clear, most dietary studies of carcinogenesis in laboratory rodents have involved the use of large doses of a carcinogen, which is not comparable to the human situation. The use of carcinogens has been necessary because laboratory rodents have extremely low spontaneous rates of colon cancer. Newmark et al. (2001) showed, however, that a radical dietary manipulation sufficed to induce high rates of colon cancer in C57BL/6 mice. Here we report an investigation into whether or not this dietary manipulation acts by altering somatic mutation rates. We used the transgenic lambda cII locus of F1 pups (C57BL/6 x Big Blue with the same C57BL/6 genetic background. The same diet (ND), high in fat, and low in calcium, vitamin D, folic acid, choline, and fibre, that was used by Newmark et al. (2001) was fed ad libitum to dams during pregnancy and lactation in order to examine its effect on mutagenesis in development and growth. There was no significant difference in mutant frequency in the small intestine (P = 0.82), or bone marrow (P = 0.95) of pups fed a ND versus the control diet. To investigate the effect of a ND during adulthood, 6-week-old F1 pups were fed a ND ad libitum for 6, 12 and 19 weeks. There was no significant difference in mutant frequency in the small intestine (P = 0.66) or colon (P = 0.49) at the cII locus with no significant difference in body weight. These results indicate that Western diet-induced carcinogenesis is not mediated by alterations in mutation rate and thus may act at the promotion rather than at the initiation stage of carcinogenesis.

Animals↗
PubMed2004

Cadmium induces DNA damage in tobacco roots, but no DNA damage, somatic mutations or homologous recombination in tobacco leaves.

The heavy metal cadmium (Cd(2+)) applied on tobacco roots in the form of cadmium chloride, induced significantly higher levels of DNA damage as measured by the cellular Comet assay than did treatment of isolated root nuclei, analyzed by use of the acellular Comet assay. DNA damage induced by Cd(2+) in roots of a transgenic catalase-deficient tobacco line (CAT1AS) was higher than in wild-type tobacco (SR1) roots. In contrast to treatment with the positive control ethyl methanesulphonate, Cd(2+) induced no significant DNA damage in leaf nuclei, and neither somatic mutations, nor homologous recombination as measured by the GUS genereactivation assay, were observed in leaves. Analysis of the accumulation of cadmium by inductively coupled plasma optical emission spectrometry demonstrates that roots accumulate almost 50-fold more cadmium than above-ground parts of the tobacco seedlings. This may explain the absence of Cd(2+) genotoxicity in leaves.

Cadmium↗
PubMed1990

Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation.

The proximate cause of autoantibodies characteristic of systemic autoimmune diseases has been controversial. One hypothesis is that autoantibodies are the result of polyclonal nonspecific B cell activation. Alternatively, autoantibodies could be the result of antigen-driven B cell activation, as observed in secondary immune responses. We have approached this question by studying monoclonal anti-DNA autoantibodies derived from unmanipulated spleen cells of the autoimmune MRL/lpr mouse strain. This analysis shows that anti-DNAs, like rheumatoid factors (19), are the result of specific antigen-driven stimulation. In addition, correlation of sequences with fine specificity shows that: (a) somatic mutations can cause specificity for dsDNA and that such mutations are selected for; (b) arginine residues play an important role in determining specificity; and (c) anti-idiotypes that recognize the majority of anti-DNA are probably not specific for any one family of V regions.

Amino Acid Sequence↗