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PubMed1999

BRCA1 and BRCA2 gene mutation analysis: visit to the Breast Cancer Information Core (BIC).

Breast cancer is a leading cancer in American women. About 7% of breast cancer is due to inheritance of mutated genes BRCA1 and BRCA2. Numerous investigations have revealed a number of mutations in BRCA1 and BRCA2 genes. The inheritance of the mutated BRCA1 or BRCA2 genes accounts for 45% and 35%, respectively, of hereditary breast cancers. A central database named Breast Cancer Information Core (BIC) has been established in the National Human Genome Research Institute (NHGRI) to coordinate the information related with BRCA1 and BRCA2 research. Nearly half of the mutations (49%) in the BRCA1 gene are frameshift mutations and the cancer-causing mutations account for 66% of all entries. However, for the BRCA2 gene frameshift mutations and cancer-causing mutations account for only 35% and 43%, respectively, of all entries. The significance of a large portion of missense sequence variants (24% of BRCA1 mutations and 47% of BRCA2 mutations) needs further evaluation. The incidence of 185delAG and 5382insC in BRCA1 gene and 6174delT in BRCA2 gene is predominantly high and the founder effect of these mutations is discussed.

BRCA2 Protein↗
PubMed1998

A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia. Mutations in brief no. 122. Online.

Hypochondroplasia and achondroplasia are skeletal dysplasias, characterized by autosomal dominant inheritance and disproportionate short stature, which occurs mainly due to growth failure of the extremities. Both dysplasias have been mapped to fibroblast growth factor receptor 3 (FGFR3) gene. For hypochondroplasia, two point mutations, both responsible for the Asn540Lys substitution in the region coding the tyrosine kinase domain have been reported. Here we report an A to G transition at position 1651, predicting an Ile538Val substitution in the FGFR3, in hypochondroplasia. The substitution is found in a swedish family with three affected members. The criteria for hypochondroplasia were disproportionate short stature and radiological evidence of shortened long bones and decrease or absence of normal increase in interpedicular distances of the lumbar column. The mutation was detected by direct sequencing and restriction enzyme Tai I digestion. The base change was not found in the FGFR3 genes of unaffected members of the family nor in seventy-five unrelated unaffected individuals, suggesting that it was not a polymorphism. The Ile538Val substitution is a conservative amino acid change (a hydrophobic amino acid incorporated for another hydrophobic amino acid). Nevertheless, it is located in the stretch of nine amino acids, which is highly conserved among all the human fibroblast growth factor receptors. Considering the location of this substitution and the segregation with the phenotype in this family, we propose that it is a causative mutation of hypochondroplasia. It is difficult to establish whether the Ile538Val substitution is rare in hypochondroplasia patients or whether the individuals, who have a moderate degree of short stature, rarely seek medical help for the short stature and consequently are rarely diagnosed as affected by hypochondroplasia.

Achondroplasia↗
PubMed2000

[18 F]-dopa PET study in patients with juvenile-onset PD and parkin gene mutations.

+Parkin gene mutations cause a form of early-onset autosomal recessive PD with neuronal loss in the substantia nigra and no Lewy bodies. The authors present a PET [18F]-dopa study of one familial and two sporadic cases with juvenile-onset PD resulting from parkin gene mutations. They found a profound decrease of [18F]-dopa uptake, representing 28% of putamen and 44% of caudate nucleus control subject values. PD caused by parkin gene mutations is distinct from idiopathic PD on molecular grounds but has similar clinical and PET findings.

Adult↗
PubMed1997

Absence of p53 gene mutations in rat colon carcinomas induced through the synergistic interaction between methylazoxymethanol and X-irradiation.

p53 is one the most frequently mutated genes found in human colonic tumors. Because colonic neoplasms induced in rats by certain chemical carcinogens are similar to human colonic tumors in their histological features and proliferation characteristics, the rat has been used as an experimental model to study the pathogenesis of colon cancer. However, p53 mutations were not detected in the chemically induced colonic tumors analyzed for p53 mutations. X-irradiation has also been shown to induce colonic neoplasms in rats that resemble human colonic tumors histopathologically. Because the incidence of colonic tumors induced by methylazoxymethanol (MAM) in rats was shown to be enhanced by X-irradiation, we immunohistochemically analyzed these colonic carcinomas for the presence of p53 gene mutations. The immunohistochemical analyses clearly showed the absence of nuclear immunoreactivity in all ten tumors examined. The results from the present study indicate that point mutations in p53, at least in the coding region, are not involved in the development of colon cancer induced by the combination of MAM and X-irradiation. Our observations, together with the data from previous studies, further suggest that rat colon carcinogenesis, unlike human colon cancer, may not involve p53 mutation as an obligatory event.

Adenocarcinoma↗
PubMed1999

H-ras and K-ras gene mutations in primary human soft tissue sarcoma: concomitant mutations of the ras genes.

ras gene mutations have been described with varying frequency in several types of human malignancies. To determine the incidence and type of ras mutations in human soft tissue tumors, we studied 45 sarcomas, including 27 malignant fibrous histiocytomas (MFHs), 10 liposarcomas, 2 rhabdomyosarcomas, and 6 leiomyosarcomas. Al of the tumors were investigated by direct sequence analysis with the automated DNA sequencing of polymerase chain reaction-amplified ras sequences. Twenty (44%) of the sarcomas examined harbored K-ras mutations, 18 (90%) of which were MFHs. All of the K-ras mutations were G-to-A transition mutations in the second position of codon 13 (glycine --> aspartic acid). Of the samples with K-ras activation, 7 (16% of the total of 45 tumors), including 6 MFHs and 1 leiomyosarcoma, also contained H-ras mutation. All of the tumors that showed H-ras alteration had G-to-T transversion mutations in the second base of codon 12 (glycine --> valine). These data possibly implicate that ras gene activation may be a relatively uncommon event in soft tissue tumors, with the exception of MFH. It is suggested that the oncogenic process underlying the development of tumors between these groups may be different and that ras gene mutations may play a role in the etiology and/or progression of MFH. It is noteworthy that when ras gene activation occurs in sarcoma, it predominantly affects the K-ras gene, particularly codon 13. Moreover, H-ras mutations in our samples were detected only in association with tumors that also displayed K-ras-mutated genes. This study demonstrates for the first time concomitant mutations in two different members of the ras gene family in sarcoma

Adolescent↗
PubMed1996

The photomutagenicity of fluoroquinolones in tests for gene mutation, chromosomal aberration, gene conversion and DNA breakage (Comet assay).

The ability of fluoroquinolones to cause light-induced adverse effects has been established in experimental studies and clinical observations. The formation of active oxygen species appears to be responsible for this activity. Photomutagenicity tests with bacterial, lower eukaryotic and mammalian cells were performed with three fluoroquinolones (Fleroxacin, Ciprofloxacin and Lomefloxacin). After concomitant irradiation with simulated solar light (with a reduced UVB component), weak increases in the number of revertants were observed in Salmonella typhimurium TA104 and TA100. No photomutagenic activity was detected in Saccharomyces cerevisiae D7. In the chromosomal aberration (CA) test with Chinese hamster V79 cells the number of aberrant metaphases was markedly increased. In the Comet assay with mouse lymphoma cells, evidence of extensive DNA breakage was obtained. All three compounds showed similar potencies in the Comet and Ames assays while there was a clear gradation of potencies in the CA assay (Lomefloxacin > Fleroxacin > Ciprofloxacin), which conformed with reports on the relative potencies regarding phototoxicity. The oxygen radical scavengers catalase, superoxide dismutase and N, N'-dimethylurea modulated the photoclastogenicity and phototoxicity but had no influence on the effects in the Comet and Ames tests. It thus appears that different kinds of mechanism are responsible for toxicity and clastogenicity on the one side and DNA breakage and gene mutation on the other side. Pre-irradiation of the test articles did not lead to enhanced genotoxicity, indicating the involvement of very short lived genotoxic agents. The results endorse the advice to avoid excessive light exposure during antibiotic therapy with fluoroquinolones.

Animals↗
PubMed2000

p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma.

P16 and P14ARF are two tumor suppressors encoded by the locus ink4a-arf which is frequently deleted in human tumors. Recent experiments performed with mouse embryonic fibroblasts have shown that P14ARF is an upstream regulator of the P53 pathway. This raises the question as to whether in human tumors the loss of p14arf and mutation of p53 are mutually exclusive events which segregate with genetic alterations at other loci. To examine this question we performed a multigenic analysis on 29 gliomas. We analysed p53 and p14arf in relation with five other genetic loci encoding the most frequently mutated genes in human gliomas: cdkn2a, mdm2, egfr, pten and the chromosomal regions 10q23.3 and 10q25-26. Our study shows for the first time that p53 mutations and p14arf deletions appear mutually exclusive in human glioblastoma, suggesting that they may be functionally redundant in glioma tumorigenesis. The P53 pathway is, therefore, disrupted in 81.8% of malignant gliomas (WHO grades III and IV), either by mutation of the p53 gene (31.8%) or by p14arf deletion (54.5%). These tumors further showed MDM2 overexpression (9.1%), egfr oncogene amplification/egfr overexpression (50%), pten mutations (27.3%) and loss of heterozygosity (LOH) at the chromosomal regions 10q23.3 (86.4%) and 10q25-26 (100%). These alterations did not segregate with p53 mutations or p14arf deletions, while p14arf and cdkn2a were always deleted.

Animals↗
PubMed2002

MEFV gene mutations in familial Mediterranean fever phenotype II patients with renal amyloidosis in childhood: a retrospective clinicopathological and molecular study.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurring attacks of fever and serositis. The definition of the mutated gene has allowed molecular diagnosis of the disease. The most important complication of FMF is the development of AA type secondary amyloidosis. In a group of patients clinically designated as phenotype II amyloidosis patients, renal amyloidosis develops without being preceded by typical attacks of the disease. In this study, the mutations of the MEFV gene were analysed in a group of patients clinically recognized as phenotype II. METHODS: DNA samples were obtained from tissue samples of the subjects. PCR-RFLP methods were used to analyse the M694V, M680I, V726A and E148Q mutations that have been previously defined by us to be the most common mutations in our Turkish cohort. RESULTS: The distribution of the four most common mutations among phenotype II patients was 38% for M694V, 8% for M680I, 4% for V726A and 4% for E148Q. CONCLUSIONS: In phenotype II amyloidosis patients, the distribution of the four common MEFV mutations was not significantly different from that found in all FMF patients with typical symptoms who do or do not develop amyloidosis. We therefore suggest that secondary genetic or environmental factors are operative in the development of secondary amyloidosis in patients with FMF.

Adolescent↗
PubMed1996

[Detection of the mutational gene in phenylketonuria and prenatal diagnoses by using single strand conformation polymorphism methods].

OBJECTIVE: To establish rapid methods for the detection of gene mutations and prenatal diagnosis of phenylketonuria (PKU). METHODS: The single strand conformation polymorphism (SSCP) combined with silver staining technique were used to screen the mutations in the four exons of phenylalanine hydroxylase (PAH) gene. After the polymerase chain reaction, the DNA fragments were separated by electrophoresis on polyacrylamide gel containing glycerol and visualized by silver staining. RESULTS: Three known missense mutations which are R243Q (E7)[CGA(Arg243)-->CAA (Gln)], R413P(E12) [CGC(Arg413)-->CCC(Pro)] and Y356X(E11)[TAC(Tyr156)-->TAA(Ter)] were detected in 21 degrees C, 28 degrees C and 7 degrees C. Three kinds of unknown abnormal DNA bands in exon 10 were detected in 21 degrees C. The mutations of 13 PKU families have been detected. Prenatal gene diagnoses were successfully performed in 5 pregnancies at risk with PKU. CONCLUSION: The method is very useful for detecting the mutations and prenatal diagnoses of PKU families.

Exons↗
PubMed2002

Mutated genes in juvenile and variant late infantile neuronal ceroid lipofuscinoses encode lysosomal proteins.

Positional cloning efforts of genes mutated in Batten disease and in the Finnish type of variant late infantile neuronal ceroid lipofuscinosis resulted in the identification of two novel genes, CLN3 and CLN5, and corresponding gene products that proved to be residents of lysosomes. Although the clinical phenotype of these NCL subtypes differs in the age of onset, average life span and EEG findings, the major component of material accumulating in patients' lysosomes is subunit c of mitochondrial ATPase in both these diseases. The CLN3 and CLN5 genes show ubiquitous expression patterns and are targeted to lysosomes in vitro, but the observed synaptosomal localization of the CLN3 protein in neurons would suggest some cell specificity in targeting and function of these proteins. So far, 31 different mutations of the CLN3 gene have been described in Batten patients, with one deletion of 1.02 kb accounting for 75% of disease alleles worldwide. Four CLN5 mutations are known, with one premature stop representing the major founder mutation in the isolated Finnish population. Functional studies of the yeast homolog of CLN3 and increased pH in patients' lysosomes would suggest an involvement of this protein in lysosomal pH homeostasis. Knock-out mouse models for CLN3 have been produced and the histopathology bears a close resemblance to human counterparts with characteristic lysosomal accumulations. Both CLN3 and CLN5 mouse models will provide experimental tools to resolve the pathological cascade in these neurodegenerative diseases.

Adenosine Triphosphatases↗
PubMed2000

A novel mutation of the ceruloplasmin gene in a patient with heteroallelic ceruloplasmin gene mutation (HypoCPGM).

We found a novel missense mutation in the ceruloplasmin (Cp) gene in a patient with the heteroallelic Cp gene mutation (HypoCPGM). The patient was a 72-year-old woman who came to our hospital with a 1-year history of postural tremor of the hands. The diagnosis was made based on serum Cp and copper readings which were about half the normal levels, as well as MRI tests of her brain which showed characteristics for hereditary ceruloplasmin deficiency (HCD), known to be caused by the homoallelic Cp gene mutation. Polymerase chain reaction (PCR)-direct sequencing analysis of the Cp gene of the patient revealed a novel point mutation, A to T, at nucleotide position 82 in Exon 1. This mutation changes the Ile28 codon (ATT) to a Phe codon (TTT) (missense mutation). PCR-restriction analysis with restriction enzyme Tsp EI for the mutation revealed that both the patient and her son were heterozygotes for the mutation.

Aged↗
PubMed1999

[p53 tumor suppressor gene mutation and prognosis in 105 cases of bladder cancer--the relationship between mutation of the p53 gene with clinicopathological features and smoking].

PURPOSE: Alterations of the p53 tumor suppressor gene are the most common genetic change detected in human cancers. The incidence of p53 gene mutation in bladder tumor patients were studied and were compared with clinicopathological findings, smoking history and prognosis. MATERIALS AND METHODS: Polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) was used for analysis from exon 4 to 9 of p53 gene in 105 cases of primary bladder tumors. RESULT: p53 matations were detected in 38 or 105 patients (36.2%). Kaplan-Meier Survival curves fo groups wit or without p53 gene mutation show a statistically significant difference (p = 0.0098). The mutation of p53 gene in stages pT 1 pT 1. pT 2, pT 3, pT 4 was found in 2 of 12 (16.7%), 8 of 32 (25.0%), 10 of 25 (40.0%), 12 of 20 (60.0%), 6 of 16 (37.5%) and in grades I, II, III, was noted in 1 of 17 (5.9%), 16 of 49 (32.7%), 21 of 39 (53.8%) cases, respectively. Significant differences were found for groups with grade I and grade II-III (p = 0.0045) cancers and in cases of superficial (stage pTa-1) and muscle-invasive (pT 2-4) tumors (p = 0.0148). However, mutation of p53 was not related to either age or sex in 105 patients. Recurrence rates in stage pTa-1 superficial tumor group with or without p53 mutation showed a statistically significant difference (p = 0.0419). No statistically significant difference was noted between p53 mutation and habitual smoking as well as durations of smoking. CONCLUSIONS: p53 mutations occur more commonly in higher grades and later stages of bladder tumors. Our results suggest that the prognostic factor is linked to not only histological findings but also to the presence of p53 mutation. The mutations of the p53 gene may be involved in the late events of tumorigenesis and might be used as good molecular markers for prognosis in bladder tumor.

Aged↗
PubMed2004

Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodents.

Studies of colon carcinogenesis in animal models are very useful to elucidate mechanisms and provide pointers to potential prevention approaches in the human situation. In the rat colon carcinogenesis model induced by azoxymethane (AOM), we have documented frequent mutations of specific genes. K-ras mutations at codon 12 were found to be frequent in hyperplastic aberrant crypt foci (ACF) and large adenocarcinomas. In addition, mutations of the beta-catenin gene in its GSK-3beta phosphorylation consensus motif could also be identified in many adenomas and adenocarcinomas, and altered cellular localization of beta-catenin protein was observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined, indicating that activation of Wnt signaling by accumulation of beta-catenin is a major mechanism in the AOM-induced colon carcinogenesis model. Frequent gene mutations of beta-catenin and altered cellular localization of the protein are also features of AOM-induced colon tumors in mice. Expression of enzymes associated with inflammation, such as inducible nitric oxide synthase (iNOS) and the inducible type of cyclooxygenase (COX), COX-2, is increased in AOM-induced rat colon carcinogenesis, and overproduction of nitric oxide (NO) and prostaglandins is considered to be involved in colon tumor development. We have demonstrated that increased expression of iNOS is an early and important event occurring in step with beta-catenin alteration in rat colon carcinogenesis. Activation of K-ras was also found to be involved in up-regulation of iNOS in the presence of inflammatory stimuli. In addition, expression levels of prostaglandin E(2) (PGE(2)) receptors may be altered in colon cancers. For example, the EP(1) and EP(2) subtypes have been shown to be up-regulated and EP(3) down-regulated in AOM-induced colon cancers in rats and mice. EP(1) and EP(4) appear to be involved in ACF formation, while alteration in EP(2) and EP(3) is considered to contribute to later steps in colon carcinogenesis. Increased expression of some other gene products, such as the targets of Wnt/beta-catenin signaling, have also been reported. The further accumulation of data with this chemically-induced animal colon carcinogenesis model should provide useful information for understanding colorectal neoplasia in man.

Animals↗
PubMed1999

[Relationship between p 53 gene mutation and MDR 1 gene expression in surgically resected non-small cell lung cancer].

The resistance of tumor cells to chemotherapeutic drugs is a major obstacle to successful cancer chemotherapy. Expression of the MDR 1 gene, which encodes for a transmembrane efflux pump (P-glycoprotein), leads to decreased intracellular accumulation and resistance to a variety of anticancer drugs. Recently, one mutant p 53 form was shown to stimulate the MDR 1 gene promoter in vitro, whereas wild-type p 53 repressed this activity. We examined the relationship between p 53 gene mutation and MDR 1 gene expression in specimens from non-small cell lung cancer patients. Tumor samples were obtained from 21 patients during surgery. Mutations of exon 5 through exon 8 of the p 53 gene were detected by the polymerase chain reaction single strand conformation polymorphism method. MDR 1 expression was semi-quantified by the reverse transcriptase polymerase chain reaction method. We identified p 53 gene mutation in samples from 7 patients. MDR 1 gene expression was observed in samples from 20 patients. The expressivity of the MDR 1 gene tended to be higher in patients with adenocarcinoma. No significant relationship between p 53 mutation and MDR 1 expressivity was observed in our study.

Adenocarcinoma↗
PubMed2000

Absence of somatic RET gene mutation in sporadic parathyroid tumors and hyperplasia secondary to uremia, and absence of somatic Men1 gene mutation in MEN2A-associated hyperplasia.

Germline mutations of the MEN1 gene are found in more than 85% of multiple endocrine neoplasia type 1 (MEN 1) patients, and germline mutations of the RET gene are found in more than 95% of multiple endocrine neoplasia type 2 (MEN2) patients. Parathyroid hyperplasia is seen in more than 90% of MEN 1 and about 15% of MEN2A patients. To date, somatic MEN1 mutations are reported in about 20% of sporadic parathyroid tumors. To elucidate the genetic basis of parathyroid tumor development, we examined somatic RET gene mutations in sporadic parathyroid tumors and hyperplasia secondary to uremia, and somatic MEN1 gene mutations in parathyroid hyperplasia from MEN2A patients. A total of 145 parathyroid tumors comprising 129 sporadic parathyroid tumors, 14 hyperplastic lesions secondary to uremia, and two hyperplastic lesions from MEN2A patients were examined. DNA was extracted from fresh frozen parathyroid tissue. Exons 2-10 of the MEN1 gene and exons 10 and 11 of the RET gene were sequenced. No somatic RET gene mutations were found in the 129 sporadic parathyroid tumors or 14 parathyroid hyperplastic lesions secondary to uremia. No somatic MEN1 gene mutations were found in the two parathyroid hyperplasia from MEN2A patients. These data suggest that RET gene mutation may not be involved in the development of sporadic parathyroid tumors and hyperplasia secondary to uremia and that MEN1 gene mutation may not be or is rarely associated with development of parathyroid hyperplasia in MEN2A patients.

Aged↗
PubMed2005

Barth syndrome: TAZ gene mutations, mRNAs, and evolution.

Barth syndrome (MIM 302060) is an X-linked condition that includes dilated cardiomyopathy, neutropenia, failure to thrive, abnormal mitochondria, and 3-methylglutaconic aciduria. The mutated gene, TAZ, first described in 1996, appeared to produce a large set of alternatively spliced mRNAs with initiations of transcription upstream of exons 1 and 3. Since then, disease-causing mutations have been found in all exons including, most recently, a missense mutation in the controversial exon 5. Because of the initially described second initiation of transcription in intron 2, with in-frame initiation of translation in exon 3, we hypothesized that subjects with mutations in exons 1 and 2 would produce more normal "short product" that might attenuate their phenotype. Moreover, it was of interest to determine which splice variants were potentially functional as exon 5 is not present in yeast and rodents, and the variant lacking this exon is the most abundant. Using RT-PCR, we characterized TAZ mRNAs in cultured lymphocytes from nine subjects with Barth syndrome and two healthy controls. The TAZ genes and mRNAs of primates were also included. We found the following: (1) there is only one site for initiation of transcription, and the normal alternatively spliced assortment is limited to full-length, delta5, delta7, delta5delta7; (2) there are two alternative splice sites within introns 1 and 2 that could potentially produce an in-frame product; (3) exon 5 evolved into "exonhood" in the primate lineage after the split between Old World monkeys and hominoid primates; and (4) our results suggest that only two functional protein variants exist in lymphocytes: delta5 and full-length. Although exon 5 does not appear to be required for TAZ function in yeast and monkeys, its evolution to a highly conserved spliced exon in hominoid primates and the recent finding of an exon 5 mutation in a patient with Barth syndrome suggest that the full-length variant is important to TAZ function.

Abnormalities, Multiple↗
PubMed1993

[Androgen receptor gene mutations and p53 gene analysis in advanced prostate cancer].

One of the most interesting but still unsolved issues in prostate cancer is the role of androgens, the androgen receptor (AR) and the p53 tumor suppressor gene in the development and/or progression of prostatic neoplasia. DNA obtained from prostate tissues of 7 normal donors, 5 BPH and 10 adenocarcinomas at different stages was amplified by the polymerase-chain-reaction (PCR). The products were analysed by single strand conformation polymorphism (SSCP), and by direct sequencing of those that displayed altered electrophoretic behavior. The molecular analysis of exons 1 to 8 of the AR gene revealed point mutations in codons 340 (exon 1) and 798 (exon 6) in 2/10 prostate carcinomas. No mutations were found in the p53 gene. Our findings suggest that mutations of the AR gene are relatively frequent in prostate cancer and may have therapeutical significance.

Base Sequence↗