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PubMed1998

Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors.

Endocrine tumors of the parathyroid and pancreas are encountered either as sporadic type or as part of multiple endocrine neoplasia type 1 (MEN 1). A high frequency of the loss of heterozygosity (LOH) has been observed in tumors of the sporadic type in the locus of the MEN 1 gene, which has recently been cloned and designated the menin gene. It would be of great interest to determine whether somatic mutations in the menin gene are responsible for the sporadic endocrine tumors. For this purpose, we have investigated the menin gene mutations in 21 sporadic parathyroid adenomas, 2 parathyroid carcinomas, 4 sporadic insulinomas, and 1 malignant VIP (vasoactive intestinal polypeptide)oma with WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, using PCR-single strand conformation polymorphism analysis and DNA sequencing. In none of these cases did the patient have a family history or other possible association with MEN 1. We have discovered somatic point mutations in two parathyroid adenomas (A340T and A541T), in one insulinoma (T429K), and in the malignant VIPoma (W198X). In addition, we have found two polymorphisms (D418D and V367V) in two parathyroid carcinomas and two parathyroid adenomas. Of these mutations and polymorphisms, three (A340T, T429K, and V367V) are first reported here, in the present article. Our results indicate that somatic mutations of the menin gene are responsible for a proportion of the sporadic parathyroid adenomas and pancreatic islet cell tumors.

Adenoma↗
PubMed1998

Low frequency of somatic mutations in the LKB1/Peutz-Jeghers syndrome gene in sporadic breast cancer.

Germ-line mutations in the LKB1 gene on chromosome 19p are responsible for most cases of the Peutz-Jeghers syndrome, in which intestinal hamartomas are associated with elevated risks of several cancer types, including breast cancer. We have evaluated the role of somatic mutations in LKB1 in breast cancer. Of 40 informative primary breast cancers, 3 showed loss of heterozygosity on chromosome 19p in the vicinity of LKB1, and no somatic mutations of LKB1 were observed in 62 primary breast cancers and 17 established breast cancer cell lines. The results indicate that mutations in LKB1 do not play an important role in the development of sporadic breast cancer.

AMP-Activated Protein Kinase Kinases↗
PubMed2006

Sporadic somatic mutation of c-kit gene in a family with gastrointestinal stromal tumors without cutaneous hyperpigmentation.

We described two members in a family with gastrointestinal stromal tumors (GISTs) without cutaneous hyperpigmentation. The patients were father and son who did not have cutaneous hyperpigmentation. Histological examination showed that these tumors were GISTs expressing CD34 and CD117. Tumor DNA extracted from paraffin-embedded specimens revealed somatic mutation with a deletion mutation at different codons in exon 11 of c-kit gene after direct sequencing analysis. No germline mutation was detected in DNA extracted from peripheral leukocytes obtained from the father and son. We propose that GISTs could be caused by sporadic somatic mutation in a family without germline mutation and hyperpigmentation.

Aged↗
PubMed1996

Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation.

Human tonsillar B cells were separated into naive IgD+CD38-CD23- (Bm1) and IgD+CD38-CD23 (Bm2), germinal center IgD-CD38+CD23- centroblasts (Bm3) and IgD-CD38+CD77- centrocytes (Bm4) and memory IgD-CD38- (Bm5) subsets. Previous IgVH sequence analysis concluded that the triggering of somatic mutations occurs during the transition from Bm2 subset into the Bm3 subset. To determine the initiation of isotype switching, sterile transcript expression was analyzed by amplification, cloning, and sequencing. A selective sterile I gamma, I alpha, and I epsilon expression was observed at centrocyte (Bm4) stage, suggesting that isotype switch is triggered within germinal centers, after somatic mutation is initiated with centroblasts (Bm3). Finally, the high level of 5'S gamma-S mu 3' DNA switching circles observed in germinal center B cells indicates that within human tonsils, germinal center is a major location for isotype switching.

B-Lymphocytes↗
PubMed1991

Molecular characterization of five human anti-human immunodeficiency virus type 1 antibody heavy chains reveals extensive somatic mutation typical of an antigen-driven immune response.

We report the heavy chain variable region sequences from the cDNAs of five previously described monoclonal cell lines producing human antibodies specific for the human immunodeficiency virus type 1 and detail the molecular characteristics, germ-line origins, and extent of somatic mutation among these antibodies. Three of the five heavy chain variable regions derive from the VHIV gene family, but each has arisen from a different heavy chain variable region (VH) gene segment within the VHIV family. In addition, one is derived from a VHI gene segment, and one is derived from a VHV gene segment. Since four of the five antibodies arise from known germ-line VH elements, a precise determination of the extent of somatic variation is possible. The amount of variation from the closest germ-line sequence ranges from 4.5% to 14.8% among these antibodies, most of which is concentrated in the complementarity-determining regions. In general, the diversity (D) segments are long, characteristic of D-D fusions and/or extensive terminal deoxynucleotidyltransferase activity; however, definitive homologies cannot be found with the known germ-line D segments. Joining (JH) gene segment utilization appears random. The use of five different germ-line VH gene segments and extensive somatic mutation provides evidence that a polyclonal, antigen-driven immune response occurs during the natural infection with human immunodeficiency virus.

Amino Acid Sequence↗
PubMed1986

Clonal recruitment and somatic mutation in the generation of immunological memory to the hapten NP.

The nucleotide sequences of the variable regions of lambda 1 chain bearing anti-NP antibodies from the secondary response of C57BL/6 mice were determined. The data indicate that the V186.2 VH gene which dominates the primary anti-NP response is expressed in nine out of 10 secondary response antibodies and is extensively mutated. In the V lambda 1 regions somatic mutations are less frequent. While point mutations predominate, there is suggestive evidence for two conversion events, one involving a one-codon deletion. Most, but not all, secondary response antibodies have a higher affinity (up to 10-fold) for the hapten than is seen in the primary response. The increase in affinity correlates with 'parallel' mutations in CDRs of H and L chains, likely to play a role in hapten binding. The analysis of VDJH rearrangements demonstrates that the secondary response lambda 1 chain-bearing antibodies are produced by a diverse set of B cell clones, which are only rarely expressed in primary responses. These clones are characterized by N-sequence-mediated heterogeneity in the 3' half of CDR3, where the germ line sequence of the D element DFl16.1 predominates in primary response antibodies. The antibodies analyzed in this and in previous work were isolated from idiotypically suppressed mice in order to evaluate whether, intraclonally, idiotype suppression selects antibody mutants into the memory pool, through suppression of the wild-type. A selection of this type was not detectable. However, idiotype suppression may control the pattern of clonotypes expressed in the primary versus the secondary response.

Animals↗
PubMed2000

Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine.

Somatic mutation accumulation has been implicated as a major cause of cancer and aging. By using a transgenic mouse model with a chromosomally integrated lacZ reporter gene, mutational spectra were characterized at young and old age in two organs greatly differing in proliferative activity, i.e., the heart and small intestine. At young age the spectra were nearly identical, mainly consisting of G. C to A.T transitions and 1-bp deletions. At old age, however, distinct patterns of mutations had developed. In small intestine, only point mutations were found to accumulate, including G.C to T.A, G.C to C.G, and A.T to C.G transversions and G.C to A.T transitions. In contrast, in heart about half of the accumulated mutations appeared to be large genome rearrangements, involving up to 34 centimorgans of chromosomal DNA. Virtually all other mutations accumulating in the heart appeared to be G.C to A.T transitions at CpG sites. These results suggest that distinct mechanisms lead to organ-specific genome deterioration and dysfunction at old age.

Aging↗
PubMed1997

Somatic mutations of the angiotensin II (AT1) receptor gene are not present in aldosterone-producing adenoma.

Angiotensin II stimulates aldosterone secretion from the adrenal zona glomerulosa and mediates most of its biological effects via G protein-coupled type 1 angiotensin II receptors (AT1). A number of G protein-coupled receptors are constitutively activated as a result of somatic mutations in the gene encoding the protein. It is, therefore, possible that primary hyperaldosteronism caused by an aldosterone-producing adenoma (APA) may be the result of constitutive activation of the AT1 receptor. The 1.1-kilobase coding region (exon 5) of the AT1 receptor gene was analyzed in APA and normal adrenal tissue for the presence of mutations using single stranded conformational polymorphism and sequencing techniques. In 17 APAs, no functional mutations were found that could account for the observed pathophysiology. However, three silent polymorphisms were detected in regions encoding the second extracellular loop, the intracellular arm preceding the COOH terminal, and the 3'-untranslated region. In conclusion, somatic mutations in the coding region of the AT1 receptor gene do not appear to play a role in primary hyperaldosteronism caused by an APA.

Adenoma↗
PubMed1994

Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas.

We analyzed 47 primary sporadic human renal cell carcinomas (39 clear cell and 8 non-clear cell) for mutations of the von Hippel-Lindau (VHL) tumor suppressor gene using the polymerase chain reaction and single strand conformational polymorphism analysis of DNA. All of the positive cases in single strand conformational polymorphism analyses were further characterized by direct sequencing. Somatic mutations were detected in 22 (56%) of 39 clear cell renal carcinomas including 15 deletions, 3 insertions, 3 missense mutations, and 1 nonsense mutation. Nineteen of these mutations predicted to produce truncation of the VHL protein. These mutations mainly occurred in the last one-third region of exons 1, 2, and 3. In addition, loss of heterozygosity of the VHL gene was observed in 16 (84%) of 19 informative clear cell renal carcinomas. No somatic mutations were detected in 8 non-clear cell carcinomas. These results show that the VHL tumor suppressor gene is one of the major tumor suppressor genes in human renal cell carcinomas, especially in the clear cell subtype renal cell carcinoma. Clear cell carcinoma might be distinguished from other pathological types of renal cell carcinomas by molecular genetic techniques.

Base Sequence↗
PubMed1998

Clonal overexpression of metallothionein is induced by somatic mutation in morphologically normal colonic mucosa.

Metallothionein (MT) overexpression occurs frequently in human tumours but the underlying mechanism is unknown. Morphologically normal-appearing mucosa from human colorectal carcinoma resection specimens and of the colons of ageing laboratory mice contains scattered single crypts whose cells show uniformly increased MT immunostaining, suggesting that MT overexpression arises directly from random crypt stem cell somatic mutation, followed by colonization of the clonal unit by the mutated progeny. This hypothesis has now been tested by quantifying the frequency of immunocytochemically detectable monocryptal colorectal MT overexpression, 5 and 30 days after injection of 8-week-old mice with a single dose of the mutagen dimethylhydrazine (DMH, 30 mg/kg subcutaneous). Otherwise normal-appearing MT-positive crypts were recorded as either wholly or partially involved by the overexpressing phenotype. Five days after DMH injection, the median frequency of partially involved MT-positive crypts was 11.7 x 10(-4), declining significantly to 1.8 x 10(-4) at 30 days (Mann-Whitney U, P < 0.01). In contrast, the median frequency of wholly involved crypts was 0.2 x 10(-4) at 5 days, increasing significantly (P < 0.005) to 12.9 x 10(-4) at 30 days. The frequency of MT-positive crypts and the time course of evolution of partially involved to wholly involved forms were similar to those described for mutation-induced crypt-restricted loss of glucose-6-phosphate dehydrogenase activity in mice treated with an identical DMH regimen. The findings indicate that cellular MT overexpression can occur as a direct consequence of somatic mutation, either cis-activating mutation(s) of the MT gene itself, or trans-activating mutation(s) of other genes involved in controlling MT expression. This is likely to be an important mechanism underlying MT overexpression in neoplasia. Such mutation-induced aberrant MT expression may be involved in the acquisition of selective cellular growth of survival advantage during tumour progression.

1,2-Dimethylhydrazine↗
PubMed1998

Human in vivo somatic mutation measured at two loci: individuals with stably elevated background erythrocyte glycophorin A (gpa) variant frequencies exhibit normal T-lymphocyte hprt mutant frequencies.

A survey of glycophorin A (gpa) in vivo somatic cell mutation in a population of 394 healthy people from 8 to 77 years of age (mean age +/- SD 41 +/- 15 years) revealed a subset of 37 individuals with stably elevated allele-loss and/or allele-loss with duplication variant erythrocyte frequencies (Vf) exceeding 30 x 10(-6). These 37 individuals with gpa outlier Vf are significantly older (P < 0.001) than the remainder of the larger study population from which they were drawn reflecting a highly significant increase in the prevalence of these individuals in the population beyond age 40 years. A study of hpt mutant frequencies (Mf) in the peripheral blood T-lymphocytes of 27 of these individuals, together with 15 matched control individuals with unremarkable gpa Vf, was undertaken to determine if these subjects also displayed elevated mutation frequencies at this independent locus indicative of globally elevated somatic mutation. The hprt Mf in these 27 subjects (geometric mean 11.5 x 10(-6)(dispersion interval 5.8 x 10(-6) to 22.8 x 10(-6)) was not significantly different from that observed in the 15 controls (geometric mean 12.1 x 10(-6)(dispersion interval 5.7 x 10(-6) to 25.5 x 10(-6)). These Mf are higher than typically reported values reflecting the older age distribution of these individuals (arithmetic mean age +/- SD 53 +/- 12 and 50 +/- 16 years for the subjects and controls, respectively). Taken together, these data suggest that several genetic mechanisms may be responsible for producing the gpa outlier Vf observed in these subjects. The observation that hprt Mf were not increased indicates that the majority did not arise by a genome-wide increased rate of somatic mutation detectable at both loci. The fixation and subsequent expansion of 'jackpot' mutations at the gpa locus occurring early in embryonic/fetal development also does not appear to be a predominant mechanism. Some cases may result from a stable over-representation of gpa variant cells, perhaps associated with a marked age-dependent decrease in the number of contributing erythroid stem cells in the bone marrow. The subset that displays elevated allele-loss with duplication Vf involving both gpa alleles may represent individuals with increased rates of somatic recombination. Elevations arising by this mechanism are not detected in the hprt assay, but could be confirmed using a autosomal locus in vivo somatic cell mutation endpoint such as the hla-a assay. Of primary biological significance, these results demonstrate that genetics/stochastic processes leading to the loss of heterozygosity of somatic cells occur ubiquitously in humans and in some individuals this level of somatic mosaicism can approach a frequency of 10(-3) at the gpa locus in erythroid lineage cells.

Adolescent↗
PubMed2002

High sensitivity of detection of TP53 somatic mutations by fluorescence-assisted mismatch analysis.

We analyzed exons 5-9 of the TP53 gene in 41 breast cancers using direct sequencing, PCR-SSCP (single-strand conformation polymorphism), and fluorescence-assisted mismatch analysis (FAMA), to test the level of specificity and sensitivity of each method. A major issue for the correct detection of TP53 somatic mutations in primary tumors is often represented by the large amount of normal DNA, which can cause excessive dilution of the mutant allele, with consequent possible false-negative results. High sensitivity upon dilution of the mutant allele has been demonstrated for FAMA, a method based on the chemical cleavage of a mismatch within heteroduplex DNA molecules. Exons 5-9 of the TP53 gene were analyzed by FAMA using only two long bifluorescent fragments. Differences in sensitivity, accuracy, and specificity were observed among the above-mentioned procedures. Thirteen of the 41 samples (31.7%) revealed TP53 genetic alterations by automated sequencing, 19 samples (46.3%) were positive for SSCP, whereas 14 samples (34%) showed variants detectable by FAMA. Seven samples were positive in SSCP, but negative in both FAMA and sequencing assays; however, 2 SSCP-negative samples revealed evident signals by FAMA, indicating the presence of TP53 mutations. One of the latter samples showed the alteration by sequence analysis, whereas the other failed to reveal the mutation signal even by sequencing, as a consequence of the very small amount of the mutant allele resulting from the excess of contaminating normal DNA. Our results show that FAMA may represent a suitable and accurate assay for the routine diagnosis of TP53 somatic mutations in DNAs from solid tumor biopsies.

Base Pair Mismatch↗
PubMed2000

Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells.

Hodgkin and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease (cHD) are thought to be derived from preapoptotic germinal center B cells. However, little is known about the transforming events rescuing the precursor of the H/RS cells from apoptosis. Given the importance of CD95 (Apo-1/Fas)-mediated apoptosis for negative selection within the germinal center, single micromanipulated H/RS cells from 10 cases of cHD were analyzed for somatic mutations within the CD95 gene. Three clonal mutations within the 5' regions were amplified from single H/RS cells in one case. From H/RS cells of another case, two mutations within the last exon coding for the death domain were detected. About half of these H/RS cells carried a monoallelic stop-codon; the remaining tumor cells harbored a monoallelic replacement mutation. Both mutations likely impair CD95 function. Because all these H/RS cells also bear clonal mutations inactivating the IkappaB alpha gene, the IkappaB alpha mutations occurred earlier than those of the CD95 gene in the sequence of transforming events leading to cHD. In conclusion, somatic mutations of the CD95 gene occur in a fraction of cHD cases and may favor the escape of the precursor of the H/RS clone from apoptosis.

Adult↗
PubMed1995

Somatic mutation and CDR3 lengths of immunoglobulin kappa light chains expressed in patients with rheumatoid arthritis and in normal individuals.

Immunoglobulin secretion by plasma cells infiltrating synovial membranes is a prominent feature of RA. Previous analyses of a cDNA library generated from synovium of RA patient BC revealed immunoglobulin kappa light chain transcripts with extensive somatic mutation, frequent N region addition, and unexpected variation in the lengths of CDR3 regions which form the center of the antigen binding site. To determine if these characteristics are present in other individuals, we performed reverse transcription-polymerase chain reaction amplification and sequenced > or = 10 V kappa-containing amplicons from nine tissue samples: synovia of three individuals with long-standing RA (including patient BC), PBLs of two of these individuals, and PBLs or splenocytes of four normal individuals. Increased levels of somatic mutation in PBLs appeared to correlate with increased age, which may reflect accumulation of circulating memory cells and/or decreased bone marrow production of naive B lymphocytes. Two of three RA synovial samples and both RA PBL samples exhibited increased proportions of clones with unusual CDR3 lengths. Enrichment for these antibody binding sites could be due to abnormal regulation of the emerging repertoire or to selection for B lymphocytes bearing antibodies of unusual specificity, and may play a role in the pathogenesis of RA.

Adult↗
PubMed1999

Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis.

Many studies have investigated the association between alterations in the p53 gene and clinical outcome of breast cancer, and most investigators have reported poorer overall and disease-free survival (as indicated by a relative hazard (RH) greater than one) in breast cancer cases with somatic mutations in p53. However, different studies have produced widely differing RH estimates, ranging from no risk (RH = 1) to a relative hazard of 23, and not all of these results have been statistically significant. We have therefore reviewed all the published studies that have investigated the association between somatic mutations in the p53 gene and breast cancer prognosis and used standard techniques of meta-analysis to combine the results of these studies to produce a more precise estimate of the prognostic significance of p53 mutations. Eleven studies investigated overall survival in a total of 2319 unselected cases. The RH estimates from these ranged from 1 to 23.4 with a combined RH estimate of 2.0 (confidence interval 1.7-2.5). Three studies investigated the role of p53 in node-negative patients and in these, the combined estimate of RH was 1.7 (1.2-2.3). For three studies of node-positive breast cancer the combined risk estimate was 2.6 (1.7-3.9). The inclusion of p53 mutation screening in large breast cancer clinical trials seems warranted in the light of these results. Analysis of large numbers of cases matched for stage and therapy will allow definitive clarification of the value of p53 mutational status in prognostication, and possibly choice of therapy.

Breast Neoplasms↗
PubMed1990

Molecular characterization of a somatically mutated anti-DNA antibody bearing two systemic lupus erythematosus-related idiotypes.

We report the molecular characterization of 2A4, an IgG, DNA-binding antibody bearing the 3I and F4 idiotypes which are associated with anti-DNA antibodies in serum of patients with systemic lupus erythematosus (SLE). The antibody is produced by an EBV-transformed B cell line derived from a patient with multiple myeloma whose myeloma protein is also an IgG, 3I-reactive, F4-reactive, DNA-binding immunoglobulin, although the 2A4 antibody does not itself represent the myeloma protein. The 2A4 heavy chain is encoded by a VH4 gene, a D-D gene fusion and the JH6 gene; the light chain is derived from a Vk1 gene and the Jk2 gene. This is the first human antibody shown to have a CDR3 encoded by a D-D fusion. DNA sequence analysis of the 2A4 VH gene together with a Southern blot of genomic DNA probed with a 2A4 VH-specific oligonucleotide strongly suggest it to be somatically mutated. The data provide evidence that human autoantibodies can be products of somatically mutated genes and suggest that the 2A4 antibody may reflect the selective pressure of antigen.

Amino Acid Sequence↗
PubMedDate not supplied

Somatic mutations and cellular aging: two-dimensional DNA typing of rat fibroblast clones.

Aging may be explained, to some extent, as a stochastic process of macromolecular damage. The rate of such a process should then determine longevity and be genetically controlled, as can be derived from the species specificity of maximum lifespan. The genome of the somatic cell is a major candidate to study for loss of DNA sequence integrity during aging. Unfortunately, a lack of adequate techniques has thus far hampered progress in testing the aging genome for changes in its DNA sequence content. Here we discuss recently developed sophisticated technology for studying spontaneous somatic mutations in relation to aging. More specifically, we describe the use of a novel two-dimensional DNA typing technique for the analysis of fibroblast clones derived from primary cultures established from skin biopsies of rats of different ages. Preliminary data are presented indicating the occurrence of DNA sequence changes in mini- and microsatellite regions of the rat genome at an average frequency of 2.7 x 10(-3) per analyzed DNA fragment. Age-related variations in the somatic mutation frequency of these genomic regions were not observed.

Animals↗
PubMed2000

Somatic mutations of the trefoil factor family 1 gene in gastric cancer.

BACKGROUND & AIMS: There is increasing evidence that trefoil factor family 1 (TFF1) is a stabilizer of the mucous gel overlying the gastrointestinal mucosa that provides a physical barrier against various noxious agents. TFF1 knockout mice developed multiple gastric adenomas and carcinomas, suggesting that TFF1 is a gastric-specific tumor-suppressor gene. METHODS: We analyzed the somatic mutations and loss of heterozygosity (LOH) of the TFF1 gene using an intragenic polymorphic marker in 61 gastric tumors. The expression pattern of TFF1 was also examined by immunohistochemistry. RESULTS: We detected a total of 8 somatic mutations-1 (5.5%) of 18 adenomas and 7 (16.3%) of 43 carcinomas-that were all missense mutations confined to the loop I and loop II structure of TFF1. We detected LOH in 5 (1 in adenoma and 4 in cancer) of 30 (16.7%) informative gastric tumors with an intragenic polymorphic marker -2 base pairs (bp) upstream of the coding region of the TFF1 gene. Although 2 cases were noninformative, the 7 gastric cancers with mutation seemed to show the loss of the remaining allele except in 1 case, suggesting that TFF1 is a tumor-suppressor gene. We found loss of TFF1 expression in 44.2% of the gastric carcinomas, but there is no correlation between immunoreactivity and genetic alterations of the TFF1 gene. CONCLUSIONS: These results indicate that genetic alterations of TFF1 may lead to gastric mucosal barrier defects and contribute to the pathogenesis of gastric cancer.

Adult↗