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At least 865 records · Page 48Linked to original sources
PubMed1995

Microsatellite instability in gynecological sarcomas and in hMSH2 mutant uterine sarcoma cell lines defective in mismatch repair activity.

We have examined a panel of gynecological sarcomas for microsatellite instability. The genomic DNA from 11 of 44 sarcomas contained somatic alterations in the lengths of one or more di-, tri-, tetra-, or pentanucleotide microsatellite sequence markers, and 6 of these cases had alterations in two or more markers. In addition, di-, tri-, and tetranucleotide microsatellites were found to be highly unstable in single cell clones of two cell lines derived from a uterine mixed mesodermal tumor. Since such instability is characteristic of cells defective in postreplication mismatch repair, we examined mismatch repair activity in extracts made from these lines. Both extracts were repair deficient, while an extract of another gynecological sarcoma cell line not exhibiting microsatellite instability was repair proficient. The repair deficiency was complemented by a colon tumor cell extract that was defective in the hMLH1 protein but not by an extract defective in hMSH2 protein. This suggested that the defect in the uterine sarcoma line could be in hMSH2. Subsequent analysis of the gene revealed a 2-bp deletion in exon 14, leading to premature truncation of the hMSH2 protein at codon 796 and no detectable wild-type gene present. These data suggest that the microsatellite instability observed in these cell lines, and possibly in a significant number of gynecological sarcomas, is due to defective postreplication mismatch repair. There was no apparent correlation with microsatellite instability and clinical outcome.

DNA Repair↗
PubMed1995

Microsatellite instability in adenocarcinomas of the upper gastrointestinal tract. Relation to clinicopathological data and family history.

We analyzed 66 adenocarcinomas arising in the upper gastrointestinal tract for microsatellite instability at eight microsatellite loci to investigate the role of these genetic alterations in the etiology of these tumors. We identified alterations in at least one locus in 11/46 adenocarcinomas of the stomach, in 2/15 adenocarcinomas arising in Barrett's esophagus, and in 1/5 adenocarcinomas of the duodenum and jejunum. Microsatellite instability in gastric tumors was found in 5/22 of intestinal, 1/3 of mixed, and 5/21 of diffuse type tumors. No relationship to the tumor stage (TNM), age, and survival time of the patients was observed. One patient had two synchronous gastric tumors both exhibiting microsatellite instability at multiple loci. His family history revealed four individuals in the maternal line afflicted with gastric carcinoma in three generations. Our data show that microsatellite instability is a genetic event in 11 to 24% of tumors of the upper gastrointestinal tract. The observation of microsatellite instability and a familial clustering of gastric tumors may suggest a genetic predisposition for a subset of gastric tumors, which may be identified by microsatellite analysis.

Adenocarcinoma↗
PubMed1995

Microsatellite instability in adenocarcinoma of the prostate.

Instability of dinucleotide tandem repeat sequences has been reported to play a major role in the carcinogenic pathway of familial colon cancer, as well as a potential role in the carcinogenesis of other sporadic neoplasms. To determine the frequency of short tandem repeat instability in adenocarcinoma of the prostate, we studied 40 tumors that were stratified according to tumor grade. The tissue samples were screened with di-, tri- and tetranucleotide markers spanning a wide range of chromosomal loci, including an androgen receptor gene trinucleotide repeat. Microsatellite instability was observed overall in only one of the 40 (2.5%) prostate adenocarcinomas studied. This replication error-positive tumor demonstrated repeat length alterations at two loci. Five other tumors showed an alteration in microsatellite size at a single locus. These tumors were not considered to have the microsatellite instability phenotype. All changes were identified either within tetranucleotide sequences or within the androgen receptor gene repeat (4 or 20 total markers analyzed). Both repeat length expansions and contractions were identified. The replication error-positive case also included separate metastatic nodal tissue. Additional microsatellite analysis of the metastatic tumor tissue revealed allelic patterns identical with the normal tissue control. Our data indicate that microsatellite instability is rare in prostate adenocarcinoma. Therefore, observation of this low replication error frequency suggests that most prostate carcinomas develop in the absence of widespread accumulation of somatic mutations in short tandem repeat sequences. Additionally, these genetic alterations appear to occur more often in tetranucleotide repeat sequences as well as in an androgen receptor gene trinucleotide repeat.

Adenocarcinoma↗
PubMed1995

[A new type of locus-specific instability in Drosophila melanogaster not dependent on P-M hybrid dysgenesis].

In analysis of instability at loci yellow and scute, induced by introduction of the active P-element transposase into the genome of line y2nsscme, alleles of these loci with transposase-independent instability were selected. The mutation rate of these alleles reached tens of percent. Two types of transposase-independent instability were described: (1) instability limited to the scute locus and (2) instability at both yellow and scute loci.

Alleles↗
PubMed1995

Microsatellite instability in human cancer.

Tumorigenesis has made tremendous progress through the recent identification of widespread alterations in tumor genomes, manifested as microsatellite instability. Several genes causing microsatellite instability have already been identified. This was considerably facilitated by the knowledge of homologous DNA mismatch repair genes in bacteria and yeast. Correspondingly, the human genes are also tightly linked to DNA mismatch repair. In addition, recent research showed that there must be other--yet unknown--genes that might also cause the genotype of microsatellite instability. Microsatellite instability has also provided a model for the proposed existence of mutator phenotypes by giving an explanation as to how the high number of mutations observed in malignant cells might accumulate. This review focuses on these genes and our current knowledge of their role in tumorigenesis and/or tumor progression. In addition, the occurrence of microsatellite instability in a large variety of tumors is reviewed in detail.

Base Composition↗
PubMed1996

Evidence for genomic instability in human colonic aberrant crypt foci.

Aberrant crypt foci (ACF) are morphologically abnormal structures that can be identified in whole amounts of colonic tissue from rodents treated with colon carcinogens and from patients at risk for development of colon tumors. ACF are heterogeneous and exhibit properties, such as altered patterns of cell proliferation, the presence of dysplasia, and mutations in protooncogenes and tumor formation. In this study, we have investigated the presence of genomic instability in DNA isolated from human ACF from patients with colon cancer. Altered allele length detected by electrophoretic separation of PCR amplified oligo A or microsatellite loci was used to identify candidate samples which were then more rigorously investigated by sequence analysis for instability. Of 20 patients examined, two exhibited alterations at two loci, and this instability could be confirmed by sequence analysis. An additional seven of the 20 patients had evidence for instability at a single locus. Quantitative sequence analysis of the DNA from an ACF of one of these seven patients was consistent with alteration of allele length in this patient, but the alteration was not sufficiently different from normal to reach statistical significance. Thus, genomic instability, manifest as altered length of microsatellite and oligo A sequences, in present in some ACF, and therefore can be a very early event in the development of some human colon cancers.

Adult↗
PubMed1996

Microsatellite instability in aberrant crypt foci from human colons.

Aberrant crypt foci (ACF) are distinct microscopic lesions of the colon thought to be the earliest identifiable precursors of colon cancer. As precursors of colon cancer, ACF may contain mutations in genes that are altered early in colorectal tumorigenesis. Candidates for these genes include APC, K-Ras, and those of the DNA mismatch repair system. Some colon cancers with mutations in DNA mismatch repair genes are characterized by genomic instability at simple repeated sequences, also known as microsatellite instability. In this study, we analyzed 19 ACF (> or = 20 crypts/focus) and adjoining, microscopically normal colonic mucosa from 10 colon cancer patients for the presence of microsatellite instability. DNA from two ACF from two different patients displayed microsatellite instability. None of the DNA samples from normal mucosa displayed microsatellite instability. These observations support the role of ACF as a precursor to colon cancer and provide some evidence that mutations in DNA mismatch repair genes are early somatic events in colon cancer.

Colon↗
PubMed1977

[Instable angina pectoris and the pre-infarct condition].

The instable angina pectoris belongs to the prodromes of an acute transmural my ocardial infarction, to which we refer every fresh angina pectoris, increase and prolongation of the anginous pain after stress and the appearance of pain in rest. Retrospectively we established the instable angina pectoris in 45% of the cases of a transmural myocardial infarction. Prospectively the syndrome of the instable angina pectoris was followed by a transmural myocardial infarction in 18%. In 14% of the cases with instable angina pectoris without provable transmural myocardial infarction a sudden heart death took place. In the discussion the author deals with questions of the not clarifyed pathogenesis and therapy. The instable angina pectoris is, indeed, an important clinical syndrome, but from the point of view of the short-time prognosis in our opinion it has not the presumed significance for the development of the transmural myocardial infarction and the sudden heart death.

Acute Disease↗
PubMed1996

Genetic instability and the development of recurrence of primary tumor and second primary tumor during head and neck tumorigenesis.

To determine whether the degree of genetic instability is associated with the development of recurrence of primary tumor (RPT) and second primary tumor (SPT), we examined 46 cases of head and neck squamous cell carcinomas (HNSCC) by nonisotopic in situ hybridization using chromosome specific DNA probes for chromosome 9 and 17. Forty-six cases were classified into three groups; group I, 15 cases without developing RPT and SPT; group II, 21 cases with RPT, and group III, 10 cases with SPT. We demonstrated the statistical significant increment of genetic instability in terms of normalized chromosome index (NCI) and polysomy index (PI) of chromosome 9 and 17 from normal adjacent to malignant lesions (ANL), to hyperplasia (HYP), to dysplasia (DYP), to squamous cell carcinomas (SCC). Our results demonstrated the trend of increased chromosome indices as the tissue progressed from ANL to SCC in group II over group I. However, when we compared the genetic instability between group I and the specimens from the patients who developed RPT within 6 months (group III), we found the significant increment of PI of both chromosome 9 (0.84 +/- 0.54 vs 1.25 +/- 0.46, p = 0.10) and 17 (1.02 +/- 0.62 vs 1.89 +/- 0.87, p = 0.06) on ANL in the later group. Our results also demonstrated the higher trend of genetic instability on ANL in group III over group I as shown by the statistical significance of NCI of both chromosome 9 (0.98 +/- 0.12 vs 1.06 +/- 0.02, p = 0.05) and 17 (1.02 +/- 0.09 vs 1.10 +/- 0.05, p = 0.05). These results suggested that the degree of genetic instability might be used as a potential molecular marker for the risk assessment of early RPT and SPT development during head and neck tumorigenesis.

Adult↗
PubMed1997

Developments in our understanding of detrusor instability.

It is important to recognize that our understanding of detrusor instability is far from complete. Although the significance of some of the abnormalities reported is unclear, it is likely that several factors will eventually be found to contribute to the overall clinical picture. Nevertheless, there is increasing evidence that the development of post-junctional supersensitivity of the detrusor muscle is implicated in each of the clinical subgroups of instability. Partial denervation of the detrusor appears to be the mechanism responsible for this in obstructive detrusor instability, but other abnormalities causing a chronic decrease in the excitatory motor innervation to the detrusor (e.g. decentralization, pre-synaptic inhibition) could produce similar effects and may therefore be involved. This evidence of a specific abnormality at the cellular level offers scope for therapy for detrusor instability with a new range of drugs, using agents that hyperpolarize the detrusor muscle membrane or modify calcium activation. However, bladder specificity remains a fundamental problem in the development of effective therapeutic agents for detrusor instability and poses the great challenge for the future.

Animals↗
PubMed1997

[What's new about microsatellite instability significance in human carcinogenesis?].

Microsatellite instabilities (MIN) represent a new type of mutation characterized by genomic instability (or replication error phenotype, RER+). First identified in sporadic and familial colorectal tumors, the RER+ phenotype has been sought in multiple types of cancers. Thus, two types of instability mechanisms have been shown: one due to inactivation of the mismatch repair system (phenotype RER+) and a second still unclear (instability of tri- and tetra-nucleotide repeats). In both cases, MIN seem to be the reflect of a new tumorigenesis pathway. In the context of mismatch repair defect, numerous observations show that, although instabilities seem to be random, they play a direct role in the tumoral process by altering genes that control cell growth and apoptosis. Today, MIN, as well as the detection of mutations in the DNA mismatch repair genes, can be used as diagnosis tools in oncology and provide usefull indications to adapt the chemotherapy to the disease.

Cell Division↗
PubMed1998

[Telomerase activity and genomic instability in colorectal cancers].

In this study, we investigated the correlation between the telomerase activity and the microsatellite instability in colorectal cancers and adenomas. Telomerase activity was detected in 75% of cancers and in 33% of adenomas. Microsatellite instability was detected in 24% of sporadic cancers, in 54% of multiple cancers, and in 22% of adenomas. Telomerase activity and microsatellite instability were independent events in colorectal carcinogenesis. The patients with telomerase activity and microsatellite instability showed poor prognosis. These results indicate that colorectal cancers with both telomerase activity and microsatellite instability may have more malignant potential, and adenomas with both them may be more intensive precursor of colorectal cancers.

Aged↗
PubMed1997

Microsatellite instability is correlated with lymph node-positive breast cancer.

We analyzed 81 cases of primary breast carcinoma and 7 cases of fibroadenoma for microsatellite instability at eight loci. Twenty-seven cases (33.3%) manifested aberrant microsatellite alleles: 7 (8.6%) at one locus and 20 (24.7%) at two or more loci [tumors with replication error-positive (RER+) phenotype]. No evidence of microsatellite instability was observed in fibroadenomas. We investigated correlations between RER+ phenotype and clinicopathological characteristics of the carcinomas. The RER+ phenotype was statistically associated with large tumor diameter; of 19 RER+ tumors with measured size, 16 were > 2 cm, compared to 28 of 58 tumors with no evidence of microsatellite instability or with shifts in allele sizes limited to one locus (P </= 0.005, chi2 test). Consistently, there was also a strong statistical association between RER+ phenotype and lymph node metastasis; 14 of 19 RER+ tumors with known lymph node status were N+, compared to 15 of 59 tumors with no evidence of microsatellite instability or with allele shifts limited to one locus (P </= 0.0002, chi2 test). Correlations with age of patients, proliferative activity, histotype (ductal versus lobular), and grade of differentiation were not statistically significant, although the RER+ phenotype was more frequent in lobular and high-grade ductal carcinomas, in carcinomas with high proliferative activity, and in carcinomas from patients </=50 years. Data concerning cancer(s) in first and/or second degree relatives were available for 66 cases, including 33 positive and 33 negative for family history of cancer. No correlations were detected between RER+ phenotype and family history of cancer. In conclusion, our results indicate that in breast cancer, microsatellite instability is associated with clinicopathological parameters that are considered predictors of recurrent disease and aggressive behavior.

Adult↗
PubMed1998

Suppressive effect of low-dose preirradiation on genetic instability induced by X rays in normal human embryonic cells.

The effect of low-dose preirradiation on the susceptibility of cells to radiation was examined in normal human embryonic cells exposed to X rays. Cells became significantly resistant after low-dose preirradiation when cells were irradiated with 2 cGy of X rays 5 h before exposure to 6 Gy of X rays. We found that the frequency of giant cells in the colonies surviving 6 Gy, which was the marker for genetic instability, was slightly lower compared to cells without low-dose preirradiation. The cloning efficiencies of cells surviving 6 Gy of X rays were consistently lower than those of the control cells during the successive transfer; they were increased slightly by low-dose preirradiation, although the increase was not significant. As genetic instability is not expressed uniformly among the progeny, the effect of low-dose preirradiation was examined in individual colonies surviving 6 Gy of X rays with or without preirradiation. Genetic instability, as judged by chromosome bridge formation in anaphase in each growing colony, was reduced significantly by preirradiation (P < 0.001, Wilcoxon test), and only 39% of the colonies receiving preirradiation showed instability compared to 61% of those surviving 6 Gy of X rays alone. These results suggest that low-dose preirradiation causes an increase in the amount of DNA damage that is repaired, which potentially causes genetic instability among the progeny of surviving cells.

Adaptation, Physiological↗
PubMed2025

Characterization of oncohistone H2B variants in Schizosaccharomyces pombe reveals a key role of H2B monoubiquitination deficiency in genomic instability by altering gene expression.

Various amino acid substitutions commonly occur at one residue of a histone in human cancers, but it remains unclear whether these histone variants have distinct oncogenic effects and mechanisms. Our previous modeling study in the fission yeast Schizosaccharomyces pombe demonstrated that the oncohistone mutants H2BG52D, H2BD67N, and H2BP102L cause the homologous recombination defects and genomic instability by compromising H2B monoubiquitination (H2Bub). However, it is unknown whether other amino acid changes at the H2B-Gly52/Asp67/Pro102 residues influence H2Bub levels and whether they cause genomic instability by altering H2Bub-regulated gene expression. Here, we construct diverse oncomutants at the sole H2B gene htb1-Gly52/Asp67/Pro102 sites in S. pombe and study their impacts on genotoxic response, H2Bub levels, and gene expression. Interestingly, the oncomutants htb1-G52D, htb1-D67N, and htb1-P102L exclusively exhibit significant genotoxic sensitivity, reduced H2Bub levels, and altered gene expression. These defects can be rescued by restoring H2Bub levels with the deletion of the H2B deubiquitinase ubp8+. These strong genetic correlations suggest that H2Bub deficiency plays a determinant role in the genomic instability of htb1-Gly52/Asp67/Pro102 oncomutants and that the alteration of gene expression due to reduced H2Bub levels is a novel mechanism underlying the genomic instability caused by htb1-G52D, htb1-D67N, and htb1-P102L oncomutations.

Schizosaccharomyces↗
PubMed2004

Genetic instability and transitional cell carcinoma of the bladder.

The development of cancer occurs in a stepwise fashion, with each step representing the mutation in one of several key genes. However, the mutation rate of somatic cells is too low to account for the number of mutations required for a cell to undergo carcinogenesis. Thus, the development of genetic instability is a vital early step towards carcinogenesis. We review the evidence for genetic instability, with particular reference to transitional cell carcinoma of the bladder. Both microsatellite instability and chromosomal instability are present in this tumour, and we discuss their incidence and clinical implications.

Carcinoma, Transitional Cell↗
PubMed2006

[Study on genetic instability of nm23H1 gene in Chinese with original gallbladder tumor].

The aim of this study was to examine the microsatellite instability (MSI) and loss of heterozygosity (LOH) of locus D17S396 on chromosome 17 and their influence on the expression of nm23H1 in gallbladder tumors, which may provide experimental basis for the tumor occurrence and metastasis. Techniques such as DNA extraction from formalin-fixed paraffin-embedded tissues, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), ordinary silver stain were used to study MSI and LOH of locus D17S396. Envision immunohistochemistry and Leica-Qwin computer imaging techniques were used to assess the expression of gene nm23H1. In our experiment, the frequency of genetic instability of malignant gallbladder tumors was 42.55%, which was higher than that of gallbladder adenomas, while there were no genetic instability occurred in chronic cholecystitis tissue. The frequency of LOH seemed higher with the deteriorism of gallbladder tumor. Among 47 gallbladder carcinomas, the frequency of LOH and MSI were different between different differentiation cases (P < 0.05), and the frequency of LOH in liver and lymph node metastasis cases was significantly higher than those without metastasis (P < 0.01). Moreover, the frequency of LOH was higher in stage Nevin IV and V when compared with stage I, II and III. However, the frequency of MSI showed contrary correlation with some clinicopathologic characteristics. The expression of nm23H1 in gallbladder carcinoma, gallbladder adenoma and chronic cholecystitis tissue were different (P < 0.05). The case with lymph node metastasis showed significantly lower nm23H1 expression than those without lymph node metastasis (P < 0.01). Nevin stage IV and V also exhibited lower nm23H1 expression levels compared with stage I, II and Ill. Furthermore, there was no difference in nm23H1 protein expression intensity analyzed by computer imaging techniques. In gallbladder carcinomas, the positive frequency of nm23H1 protein in LOH positive group was lower than that of LOH negative group (P < 0.05). The results indicated that the genetic instability of nm23H1 gene might be implicated in pathogenesis and progression of gallbladder tumor. Both MSI and LOH of nm23H1 gene controlled the development of gallbladder tumor independently in different paths. MSI may be an early stage molecule marker of gallbladder carcinoma. LOH may be molecule marker for the deteriorism of gallbladder tissue, which could inhibit the expression of nm23H1 in local tissue of gallbladder carcinoma and endow it with high aggressive and poor prognosis. Increasing the amount of nm23H1 protein expression could effectively restrain gallbladder carcinoma metastasis and improve prognosis of patients.

Adult↗
PubMed2004

Does this patient have an instability of the shoulder or a labrum lesion?

CONTEXT: History taking and clinical tests are commonly used to diagnose shoulder pain. Unclear is whether tests and history accurately diagnose instability or intra-articular pathology (IAP). OBJECTIVE: To analyze the accuracy of clinical tests and history taking for shoulder instability or IAP. DATA SOURCES: Relevant studies identified through PubMed, EMBASE, CINAHL, and bibliographies of known primary and review articles. STUDY SELECTION: Studies comparing the performance of history items or physical examination with a reference standard were included. Studies on fibromyalgia, fractures, or systemic disorders were excluded. Of 1449 articles, 35 were eligible, and 17 were selected. DATA EXTRACTION: Data were extracted on study population, clinical tests, reference tests, and outcome. The studies' methodological quality (patient spectrum, verification, blinding, and replication) was assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist. DATA SYNTHESIS: Six tests showed positive likelihood ratios (LRs) and confidence intervals (CIs). Tests favoring the diagnosis for establishing instability included: relocation (LR, 6.5; 95% CI, 3.0-14.0) and anterior release (LR, 8.3; 95% CI, 3.6-19). Tests showing promise for establishing labral lesions included: the biceps load I and II (LR, 29; 95% CI, 7.3-115.0 and LR, 26; 95% CI, 8.6-80.0), respectively, pain provocation of Mimori (LR, 7.2; 95% CI, 1.6-32.0), and internal rotation resistance strength (LR, 25; 95% CI, 8.1-76.0). The apprehension, clunk, release, load and shift, and sulcus sign tests proved less useful. Results should be cautiously interpreted because studies were completed in select populations in orthopedic practice, mostly assessed by the test designers, and evaluated in single studies only. No accuracy studies were found for history taking or for clinical tests in primary care. CONCLUSIONS: Shoulder complaints are frequently recurrent. Instability might cause some of these complaints. Best evidence supports the value of the relocation and anterior release tests. Symptoms related to IAP (labral tears) remain unclear. Most promising for establishing labral tears are currently the biceps load I and II, pain provocation of Mimori, and the internal rotation resistance strength tests.

Cartilage, Articular↗