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At least 1,063 records · Page 59Linked to original sources
PubMed2003

Allelic loss on chromosome 13q14 and mutation in deleted in cancer 1 gene in esophageal squamous cell carcinoma.

Previous studies have shown frequent allelic loss on chromosome 13 in esophageal squamous cell carcinoma (ESCC). We assessed the frequency of allelic loss on chromosome 13q14 and mutations of deleted in cancer 1 (DICE1) (also found on 13q14) in ESCC patients to determine if this candidate tumor suppressor gene has a role in the development of ESCC, and whether this gene was an inactivation target for allelic loss on chromosome 13q14. Initially, we examined allelic loss at five markers flanking DICE1 in 56 ESCC patients from Shanxi Province, China, and then examined the entire coding sequence of this gene for mutations using polymerase chain reaction-single-strand confirmation polymorphism (PCR-SSCP) analysis and DNA sequencing. Subsequently, we extended our evaluation to an additional 80 ESCC patients and 232 healthy individuals to confirm the germline variant found in the initial 56 ESCC patients. The frequencies of allelic loss were 71, 58, and 75% for D13S325, D13S757, and D13S887, respectively, in the initial 56 ESCC patients studied. Overall, 73% of informative patients had loss of heterozygosity (LOH) for at least one of these three markers. Somatic mutations were identified in three patients (3/56, 5%), and one novel polymorphism was identified in 3% of ESCC patients (4/136) and 3% of healthy individuals (6/232). We conclude that DICE1 mutations occur in ESCC but are infrequent. The candidate tumor suppressor gene corresponding to the frequent allelic loss on chromosome 13q14 in ESCC remains unknown.

Alleles↗
PubMed1985

Molecular analysis of an EL4 cell line that expresses H-2Db but not H-2Kb or beta 2-microglobulin.

EL4/Mar is a variant cell line that expresses H-2Db but neither H-2Kb nor beta 2-microglobulin (beta 2m). Southern and RNA blot analysis and immunoprecipitation of metabolically labeled proteins established that the B2m gene(s), beta 2m mRNA, and beta 2m protein are normal in this cell line. Somatic cell hybridization showed that the defect in this cell line was in the synthesis of H-2Kb, and RNA blot analysis with an H-2Kb specific oligonucleotide established that the H-2Kb gene(s) in this cell line was not transcribed into a stable mRNA species. The apparent absence of beta 2m on the surface of this cell line suggests that there may be some feature of the H-2Db molecule that allows it to be expressed in the absence of detectable beta 2m.

Animals↗
PubMed2006

Genetic polymorphism of metabolic enzymes modifies the risk of chronic solvent-induced encephalopathy.

In the present study, we investigate whether genetic polymorphism in enzymes involved in the metabolism of organic solvents influences susceptibility to chronic solvent encephalopathy (CSE), which is one of the major effects of long-term exposure to organic solvents. Polymorphisms in the genes encoding CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1 enzymes were determined in a group of male CSE patients (N=97) and controls (N=214). The selection of the patients was based on a standard diagnostic protocol, including interviews, neuropsychological tests and questionnaires directed to somatic, cognitive and mood symptoms and exposure, in combination with well-defined decision rules. As controls, healthy workers of similar socio-economic background, without memory problems and with no known exposure to organic solvents, were included in the study. Comparing patients and controls, higher frequencies of the variant *5B allele of the CYP2E1 gene (OR: 5.8; 95% CI: 1.8-18.8) and of the variant GSTP1*C allele (OR: 0.40; 95% CI: 0.17-0.94) were found. Homozygous carriers of the exon 4 EPHX1 Arg139 variant allele had a lower risk (OR: 0.25; 95% CI: 0.06-1.13). The present study indicates that genetic polymorphism of CYP2E1, EPHX1 and GSTP1 modify the risk of developing CSE.

Adult↗
PubMed2001

Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas.

Ovarian carcinomas (OCs), particularly recurrent OCs, are frequently resistant to transforming growth factor (TGF)-beta-mediated growth inhibition. Mutations in the TGF-beta receptor type II (TbetaR-II) gene are only evident in a minority of OCs, suggesting that other alterations of the TGF-beta signaling pathway may be involved in OC. Using PCR, cold single-strand conformation polymorphism, and DNA sequencing, we now show that 33% of primary OCs (10 of 30) harbor somatic changes in exons 2, 3, 4, and 6 of the TGF-beta receptor I (TbetaR-I) gene. Most of the changes are missense mutations and clustered largely in the catalytic domain of the receptor kinase. Interestingly, seven additional cases (23.3%) showed heterozygous carriers of an allelic variant [a 9-nucleotide deletion, del(GGC)(3)] in exon 1 of the TbetaR-I gene. This is in contrast with 10.6% of del(GGC)(3) heterozygous carriers in a recent report of a large normal population (n = 735; B. Pasche et al., Cancer Res., 59: 5678-5682, 1999). These results indicate that TbetaR-I is frequently mutated in OC and suggest that resistance to TGF-beta-mediated growth inhibition may frequently involve alterations of the TbetaR-I gene.

Adult↗
PubMed1992

[Clinico-electrophysiological characteristics of women--heterozygote carriers of fragile X chromosome].

Overall 21 women, heterozygous carriers of fragile X-chromosome (7 cases of obligate carriership and 14 sporadic cases) were examined by electroencephalography and cytogenetically. In none of them the clinical examination revealed a typical somatic appearance characteristic of Martin-Bell syndrome. Certain somatic disorders, psychasthenic traits, tearfulness and uncommunicativeness were recorded in single cases. The level of intellectual development corresponded to the low norm. Analysis of the EEG has demonstrated that in 76% of the women examined, the character of alpha-rhythm differed from normal. According to its intensity, three variants of the EEG were distinguished. In the majority of women, the EEG manifested the signs of the dysfunction of the diencephalic structures and not gross focal alterations. The character of the EEG does not provide any data which may be of diagnostic importance in revealing heterozygous carriership of fragile X-chromosome.

Action Potentials↗
PubMed1990

Review of the molecular characteristics of gene mutations of the germline and somatic cells of the human.

Molecular analyses of the limited number of de novo germinal mutations identified in humans indicate that an array of alterations in gene structure can be generated. Similar conclusions are derived from the large data set obtained from molecular analyses of alleles that segregate in the human population and cause genetic diseases. The molecular alterations include nucleotide substitutions as well as insertions, deletions and other rearrangements of the DNA. The lesions may be located in the coding or the noncoding regions of genes or may involve the flanking sequences. The insertions and deletions involve fragments ranging from single nucleotides to many kilobases, and involve both unique sequences and repetitive elements. The nature of the lesions observed to date as either de novo mutations or segregating variants suggests there are locus-specific characteristics of the alterations in DNA structure that are recovered as genetic diseases. Differences in mutation spectra among genetic loci appear to reflect both the structure of the target sequences and the relationship between gene structure and gene function. No induced germinal mutations have been identified, thus no data are available that reveal the relationships between mutagenic exposures and the molecular fingerprints of the lesion induced in the human germ cell and transmitted to the subsequent generations. In contrast, the prospects for analyzing the roles of genetic target, exposure history and individual responsiveness to exposure in creating particular molecular lesions in somatic cells are excellent, both for alterations of single nucleotides and for major alterations of gene structure.(ABSTRACT TRUNCATED AT 400 WORDS)

Alleles↗
PubMed2003

Ser217Leu polymorphism of the HPC2/ELAC2 gene associated with prostatic cancer risk in Japanese men.

The HPC2/ELAC2 gene may be associated with hereditary/familial prostate cancer (PCa). Two common missense variants (Ser217Leu and Ala541Thr) have been reported in the gene. We performed mutational, allelotyping and expression analyses and a molecular epidemiological study to clarify the relations between this gene and prostatic diseases, including PCa and benign prostatic hyperplasia (BPH) in Japanese men. We screened for mutations in 109 patients with PCa including 11 patients from 1 hereditary and 9 familial PCa. Loss of heterozygosity and expression were analyzed. An epidemiological study was done in sporadic PCa (n=98) and BPH (n=143) using 1 novel (Ser627Leu) and 2 previously described polymorphisms of the HPC2/ELAC2 gene. Somatic or germline mutations were not confirmed in any cases of PCa. Loss of heterozygosity at 2 microsatellites, D17S1289 and D17S520, was detected in 1 of 38 and 1 of 35 cases, respectively. Expression analysis revealed decreased or absent mRNA expression in 6 of 38 tumors. Epidemiologic analysis showed that a Leu allele at codon 217 was significantly more frequent in patients with PCa than in controls (10.2% vs. 3.5%, odds ratio = 3.11; 95% confidence interval, 1.22-7.90). At codon 541, all patients with PCa or BPH and all control subjects had the Ala/Ala genotype. At codon 627, the incidence of the Leu variant was slightly, but not significantly, higher in patients with BPH than in controls (7.0% vs. 2.8%, odds ratio = 2.59, 95% confidence interval, 0.94-7.13, not statistically significant). We concluded that germline/somatic mutations of HPC2/ELAC2 are uncommon in PCa. Similarly, allelic imbalances at the gene locus and changes in expression are rare. Although no difference in allele frequency at Ser217Leu between patients with PCa and controls has been reported in a Western population, this polymorphism is a potential indicator of PCa risk in Japanese men and it should be examined in other ethnic groups.

Aged↗
PubMed2001

Allelic and somatic variations in the endogenous opioid system of humans.

People with a genetic predisposition for substance abuse have defects in genes for the opioid peptides and receptors. A high number of polymorphisms have been detected in the mu-opioid receptor, some of which result in pharmacological alterations. The opioid peptide proopiomelanocortin proved extraordinarily rich in mutations that often lead to severe phenotypical consequences. Prodynorphin displays a polymorphic regulation of transcription. Variants of the mu- and the delta-opioid receptor showed positive associations with opiate and/or alcohol addiction in some studies. However, these associations were weak, indicating a small contribution of the opioid system to these disorders.

Alleles↗
PubMed1981

Isolation of somatic cell mutants defective in the biosynthesis of phosphatidylethanolamine.

An in situ autoradiographic assay for CDP-ethanolamine:1,2-sn-diacylglycerol ethanolamine phosphotransferase (EC 2.7.8.1) activity in Chinese hamster ovary cells was developed and used to screen approximately 10,000 individual mutagen-treated colonies attached to filter paper (Esko, J. D., and Raetz, C. R. H. (1978) Proc. Natl. Acad. Sci. U. S. A. 75, 1190-1193). A variant (strain 40.11) was isolated in which the ethanolamine phosphotransferase specific activity in vitro was 6-10-fold less than in the parent, but the level of CDP-choline:1,2-sn-diacylglycerol choline phosphotransferase (EC 2.7.8.2) activity was normal. In extracts, the mutant was also defective in the synthesis of ethanolamine plasmalogen. In vivo, the short term kinetics of labeling with [32P]phosphate or [14C]ethanolamine was correspondingly altered. However, the long tem growth rate and steady state phospholipid compositions of the mutant and parent were quite similar. These results show that the ethanolamine and choline phosphotransferases of Chinese hamster ovary cells are distinct as judged by genetic criteria, while the biosynthesis of phosphatidylethanolamine and its plasmalogen share common enzymatic component(s).

Animals↗
PubMed2005

Fine mapping and evaluation of candidate genes for cervical cancer on 11q23.

We previously showed that loss of heterozygosity (LOH) at 11q23 is a common genetic alteration in cervical cancer (CC) and that it correlates with extensive invasion of lymph-vascular spaces. In the current study, we looked for allelic loss in paired normal/tumor genomic DNA from 121 cervical tumors by using 20 well-mapped microsatellite markers on 11q. LOH at one or more loci was observed in 81 (66.9%) tumors. The deletion patterns in tumors are complex. However, at least three LOH islands could be defined between D11S614 and D11S4167. We also genotyped 11 CC cell lines and analyzed the results using the homozygosity mapping-of-deletions method. Five of the 11 cell lines showed continuous homozygosity that extended through 11q23.3-11q24.1. We used a candidate-gene approach to screen candidate tumor-suppressor genes (TSGs) that were localized in that region. Intragenic changes in the entire coding sequence of four candidate genes (RNF26, USP2, POU2F3, and TRIM29) in the region and a proposed TSG (PPP2R1B) centromeric to the region were evaluated. The expression status of USP2, POU2F3, TRIM29, and another proposed TSG that is telomeric to the region (BCSC1) also was examined. We identified previously described single-nucleotide polymorphisms (SNPs), several novel variants, and three rare SNPs in the five candidate genes. Decreased expression of POU2F3 and TRIM29 was found in some cervical tumors and CC cell lines. Our results indicate that a major region of LOH in cervical cancer exists within a 3.6-Mb stretch of DNA on 11q23.3-q24.1 and that somatic mutations in RNF26, USP2, TRIM29, POU2F3, or PPP2R1B probably are not important for cervical carcinogenesis.

Adenocarcinoma↗
PubMed1995

Mutations in the estrogen receptor gene.

Somatically generated mutations in the estrogen receptor (ER) have been found at the mRNA/cDNA level in human breast cancer biopsies and in established breast cancer cell lines. Aberrantly spliced ER mRNA causes the appearance of truncated or internally deleted ER protein forms. Studies on the functional activity of the ER variants in expression systems have revealed dominant-positive receptors that are transcriptionally active in the absence of estrogen, and dominant-negative receptors that are themselves transcriptionally inactive but that prevent the action of the normal receptor. The ER variants are believed to confer resistance to endocrine therapy in breast cancer patients. Abnormally spliced forms of ER, similar to those in breast cancer, have been reported in human meningiomas.

Breast Neoplasms↗
PubMed2004

BRAF mutations typical of papillary thyroid carcinoma are more frequently detected in undifferentiated than in insular and insular-like poorly differentiated carcinomas.

Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated with different histotypes of papillary thyroid carcinoma (PTC). The V599E mutation is highly prevalent in PTC with a papillary or mixed papillary follicular growth pattern, and the K600E mutation is apparently restricted to the follicular variant of PTC. It is usually accepted that thyroid malignancies may follow a progression path from well-differentiated to poorly differentiated (PDC) and undifferentiated (UC) carcinomas. One would expect that at least some of the less differentiated carcinomas would harbour the genetic alterations of pre-existing well-differentiated tumours. In order to find the prevalence of BRAF mutations in PDC and UC, we screened a series of 19 PDCs and 17 UCs, as well as 3 UC-derived cell lines, for both mutation types. The group of PDCs was restricted to the so-called insular and insular-like PDCs, thus excluding PTCs with solid, insular or trabecular foci of growth and PDCs displaying typical PTC nuclei. No BRAF mutations were detected in any of the 19 cases of PDC, whereas 6 of the UCs (35%) and one UC-derived cell line presented the BRAFV599E mutation. The BRAFK600E mutation was not detected in any case. We conclude that UC may progress from BRAFV599E-mutated PTC. The absence of BRAF mutations in our series of PDC supports the assumption that pure insular and insular-like PDCs are more closely related to follicular carcinoma than to PTC.

Adenocarcinoma, Papillary↗
PubMed1999

Absence of PPP2R1B gene alterations in primary ovarian cancers.

The PPP2R1B gene has recently been implicated as a tumor suppressor based on the finding of somatic alterations in lung and colon cancers. PPP2R1B is located on chromosome 11q22-24 which coincides with the site of frequent loss of heterozygosity (LOH) in ovarian cancer. We investigated if the PPP2R1B gene was inactivated in ovarian cancer by single strand conformational polymorphism (SSCP) and heteroduplex (HD) analysis of 99% of the coding region. LOH at the PPP2R1B locus was detected in 32% of the malignant tumors but no somatic alterations were detected in any of 65 malignant, five borderline or six benign tumors. A germline G > A transition (GGC > GAC) in codon 90 was detected in 4/76 tumors. This alteration has previously been described as a mutation but on further investigation we found that the frequency of this variant among 167 ovarian cancers (4.2%) was not statistically significantly different from that observed in 247 non-cancer random controls (2.4%). We conclude that the PPP2R1B gene is not involved in the pathogenesis of ovarian cancer. The codon 90 Gly > Asp alteration may represent a non-pathological polymorphism and consequently the mutation frequency reported in lung cancers may have been overstated and the designation of PPP2R1B as a tumor suppressor gene should be regarded with caution.

Carcinoma↗
PubMed1995

cDNA sequence and gene locus of the human retinal phosphoinositide-specific phospholipase-C beta 4 (PLCB4).

Defects in the Drosophila norpA (no receptor potential A) gene encoding a phosphoinositide-specific phospholipase C (PLC) block invertebrate phototransduction and lead to retinal degeneration. The mammalian homolog, PLCB4, is expressed in rat brain, bovine cerebellum, and the bovine retina in several splice variants. To determine a possible role of PLCB4 gene defects in human disease, we isolated several overlapping cDNA clones from a human retina library. The composite cDNA sequence predicts a human PLC beta 4 polypeptide of 1022 amino acid residues (MW 117,000). This PLC beta 4 variant lacks a 165-amino-acid N-terminal domain characteristic for the rat brain isoforms, but has a distinct putative exon 1 unique for human and bovine retina isoforms. A PLC beta 4 monospecific antibody detected a major (130 kDa) and a minor (160 kDa) isoform in retina homogenates. Somatic cell hybrids and deletion panels were used to localize the PCLB4 gene to the short arm of chromosome 20. The gene was further sublocalized to 20p12 by fluorescence in situ hybridization.

Amino Acid Sequence↗
PubMed1996

RET mutations in human disease.

The RET proto-oncogene is at the origin of one of the most interesting models of human disease caused by mutations in a receptor tyrosine kinase gene. Somatic rearrangements of RET are involved in the aetiology of a variable proportion of papillary thyroid carcinomas (PTC), the most common type of thyroid tumour whose prevalence is increasing in areas heavily exposed to radioactive fallout after the Chernobyl accident of 1986. Moreover, germline RET mutations are associated with the three variants of the inherited cancer syndrome known as multiple endocrine neoplasia type 2 (MEN2A, MEN2B and FMTC). Finally, RET mutations or heterozygous deletions of the whole gene cause the autosomal dominant form of Hirschsprung disease (HSCR), a congenital disorder of the enteric nervous system (ENS).

Animals↗
PubMed2001

Idiopathic environmental intolerances (formerly multiple chemical sensitivity) psychiatric perspectives.

Idiopathic environmental intolerances (IEI)/multiple chemical sensitivity (MCS) is characterized by various somatic symptoms which cannot be explained organically, but are attributed to the influences of toxic environmental chemicals in low, usually harmless doses. In the absence of a widely accepted definition of IEI, contradictory aetiological hypotheses and therapeutic suggestions are discussed. Some authors doubt the existence of IEI/MCS as a disease entity of its own. The label IEI does not implicate neither a diagnosis of somatic disease nor that it is caused by an avoidable exposure. Many IEI patients suffer from psychiatric diseases. A majority of them can be diagnosed as somatoform disorders. Consequently, psychiatric therapies could be effective. This review describes the current knowledge about IEI/MCS, outlines a diagnostic algorithm and a psychotherapeutic concept for variants of IEI understood as a somatoform disorder.

Comorbidity↗
PubMed1977

Detection of active heteropolymeric beta-glucuronidase in hybrids between mouse cells and human fibroblasts with beta-glucuronidase deficiency.

Heteropolymeric beta-glucuronidases are detected in somatic cell hybrids between mouse cells and human fibroblasts deficient in beta-glucuronidase (beta-D-glucuronide glucuronosohydrolase, EC 3.2.1.31) by electrophoresis and column chromatography. Specific antisera against human beta-glucuronidase prepared in mice recognize these heteropolymeric beta-glucuronidases. Our results demonstrate that synthesis of mutant subunits of variant beta-glucuronidase continues in deficient human fibroblasts; these mutant subunits of human beta-glucuronidase retain the ability to associate with normal subunits of mouse beta-glucuronidase to form the enzymatically and immunologically active tetramer. These studies demonstrate the usefulness of interspecific cell hybrids for study of structural gene mutations of polymeric enzymes, such as those of beta-glucuronidase in mucopolysaccharidosis type VII.

Animals↗
PubMed2026

PULPO: pipeline of understanding large-scale patterns of oncogenomic signatures.

SUMMARY: PULPO v1.0 is a novel; fully automated pipeline designed for the preprocess and extraction of mutational signatures from raw Optical Genome Mapping (OGM) data. Built using Snakemake and executed within an isolated, Conda-managed environment, PULPO transforms complex cytogenetic alterations, captured at ultra-high resolution, into Catalogue of somatic mutations in cancer mutational signatures (COSMIC). This innovative approach not only enables researchers to work directly from raw OGM inputs but also streamlines the traditionally complex process of signature extraction, making advanced oncogenomic analyses accessible to users with varying levels of bioinformatics expertise. By facilitating the integration of comprehensive structural variants (SVs) and copy number variants (CNVs) data with established signature catalogues, PULPO paves the way for improved diagnostic accuracy and personalized therapeutic strategies. AVAILABILITY AND IMPLEMENTATION: The pipeline is open source and freely available under the MIT License at https://github.com/OncologyHNJ/PULPO-v.1.0 and DOI in Zenodo: https://zenodo.org/records/17749097.

Software↗