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PubMed2001

p53 protein accumulation and genomic instability in head and neck multistep tumorigenesis.

Head and neck cancer develops in a multistep process and is associated with increasing frequencies of p53 alterations and with increasing genomic instability. To study the relationship of p53 alterations and genomic instability during head and neck tumorigenesis, we analyzed p53 protein expression and chromosome 9 and 17 polysomy in 48 squamous cell carcinomas of the head and neck and their adjacent normal epithelium (31 sites), hyperplastic (24 sites), and dysplastic lesions (26 sites). Normal oral epithelium obtained from seven nonsmoking, cancer-free individuals served as negative controls. Six (19%) of 31 lesions in adjacent normal epithelium, 7 (29%) of 24 hyperplastic lesions, 12 (46%) of 26 dysplastic lesions, and 28 (58%) of 48 squamous cell carcinomas expressed p53. In contrast, no normal control epithelium had detectable p53 expression. To determine the relationship between dysregulated p53 expression and genomic instability during tumorigenesis, we compared p53 immunohistochemistry distributions and chromosome polysomy levels (by chromosome in situ hybridization) in different histological groups associated with tissue progression. Although the degree of chromosome polysomy increased for all of the groups during histological progression, lesions with dysregulated p53 expression showed nearly 2-4-fold increased levels of chromosome polysomy. This trend was significant for dysplastic lesions (P = 0.005 and P = 0.002 for chromosomes 9 and 17, respectively) and for squamous cell carcinoma (P = 0.005 and P = 0.002 for chromosomes 9 and 17, respectively). Image analysis studies for 28 p53-expressing tumors and their adjacent premalignant lesions demonstrated a strong spatial correlation between stepwise transitions from low to high p53 expression and increased chromosome polysomy frequencies in 13 (46%) of 28 cases. These findings suggest that altered p53 expression is associated with increased genetic instability in preneoplastic epithelium and may play a driving force for increasing the rate of accumulation of genetic events during head and neck tumorigenesis.

Aneuploidy↗
PubMed2001

Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma.

BACKGROUND: Cells with deficient DNA mismatch repair develop microsatellite instability. Extensive microsatellite instability (MSI-high) is characteristic of colorectal carcinomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) and in 10-% 15% of sporadic colorectal carcinomas. Microsatellite instability-high colorectal carcinomas differ from others in important clinical and pathologic features. However, MSI typing is expensive and not widely available. Microsatellite instability type may be predicted by tumor-infiltrating lymphocytes (TILs), which can be evaluated with ordinary light microscopy. METHODS: The authors evaluated TILs as a pathology screen for MSI-high status in 138 colorectal carcinomas that had been evaluated for MSI in a variety of studies. This case series was systematically enriched with HNPCC and other MSI-high cases to allow accurate sensitivity and specificity estimation. Tumor-infiltrating lymphocytes were quantitated as TILs per 10 high-power microscopic fields by an observer blinded to MSI status. RESULTS: Of the 138 carcinomas studied, 67 (48.6%) were MSI-high, 22 (15.9%) were MSI-low, and 49 (35.5%) were MSI-stable. All 25 HNPCC colorectal carcinomas were MSI-high. Tumor-infiltrating lymphocytes counts ranged from 0 to 300, with a markedly skewed distribution (median, 11; mean, 36). Sensitivity and specificity for selected cut points of TIL count were computed. Using a TIL count of 5 as a cut point yields a sensitivity of 93% and specificity of 62%. In a population in which 12% were MSI-high, consideration of TIL could reduce the number of colorectal carcinomas referred for MSI testing by greater than one-half, and still 93% of the MSI-high carcinomas would be identified. CONCLUSIONS: The presence of MSI defines a subset of colorectal carcinomas with special molecular etiology and characteristic clinical, pathologic features, inclusive of increased survival. The authors conclude that quantification of TILs may provide a simple, single criterion for choosing which colorectal carcinomas are candidates for MSI testing.

Colorectal Neoplasms↗
PubMed2001

Instability of bacterial artificial chromosome (BAC) clones containing tandemly repeated DNA sequences.

The cloning and propagation of large DNA fragments as bacterial artificial chromosomes (BACs) has become a valuable technique in genome research. BAC clones are highly stable in the host, Escherichia coli, a major advantage over yeast artificial chromosomes (YACs) in which recombination-induced instability is a major drawback. Here we report that BAC clones containing tandemly repeated DNA elements are not stable and can undergo drastic deletions during routine library maintenance and DNA preparation. Instability was observed in three BAC clones from sorghum, rice, and potato, each containing distinct tandem repeats. As many as 46% and 74% of the single colonies derived from a rice BAC clone containing 5S ribosomal RNA genes had insert deletions after 24 and 120 h of growth, respectively. We also demonstrated that BAC insert rearrangement can occur in the early stage of library construction and duplication. Thus, a minimum growth approach may not avoid the instability problem of such clones. The impact of BAC instability on genome research is discussed.

Chromosomes, Artificial, Bacterial↗
PubMedDate not supplied

[Radiation-induced genomic instability: phenomenon, molecular mechanisms, pathogenetic significance].

The recent data on the radiation-induced genome instability as a special state of progeny of cells irradiated in vitro as well as after a whole body exposure to ionizing radiation, that make these cells considerably different from normal, unirradiated cells, were considered. This state presents a number of cytogenetical, molecular-biological, cytological and biochemical manifestations untypical for normal cells. The state is controlled by the mechanisms of regulation of checkpoints of cell cycle, and apoptosis, that is under gene p53 control. The proof has been found that this state transfers from irradiated maternal cells to their surviving progeny by the epigenetical mechanisms and would exist until the cells restore the original state of response on the DNA damage. From the point of view of the genome instability conception, that considers the chromatine rearrangement as the adaptive-evolution mechanism of adaptation of the species to changeable environmental conditions, the radiation-induced genome instability may be considered as transition of irradiated progeny to the state of read these to adaptation changes with two alternative pathways. The first leads to adaptation to enviromental conditions and restoring of normal cell functions. The second presents the cell transition into the transformed state with remain genome instability and with increase of tumour growth probability.

Adaptation, Physiological↗
PubMed2001

Recognition of bladder instability on voiding cystourethrography in infants with urinary tract infection.

PURPOSE: We evaluate voiding cystourethrography as a method for identifying bladder instability in infants. MATERIALS AND METHODS: Cystometry was combined with voiding cystourethrography in 79 male and 64 female infants with first time urinary tract infection. Bladder wall irregularity, elongation of bladder shape, and filling of the posterior urethra were transient radiological signs occurring during bladder filling and were considered to reflect bladder instability. A pediatric radiologist looked for these signs on all 480 films exposed during bladder filling. The results were correlated to simultaneous detrusor pressure recordings. The analysis was repeated independently by a urologist to evaluate the reliability of the radiological signs used. RESULTS: The sensitivity and specificity were both 90% in the evaluation of radiological signs of bladder instability. Filling of the posterior urethra was the least frequently reported radiological sign, which was seen at 53% of unstable contractions. However, when this sign was reported, instability was usually correctly detected (85%). Evaluation accuracy had improved with increasing numbers of noted signs per film. This accuracy had included 29%, 67% and 91% of unstable contractions that were correctly diagnosed when 1, 2 or 3 signs were noted, respectively. The number of noted signs was positively related to the strength of the unstable detrusor contraction. Urologist evaluations had similar results to the radiologist, although the sensitivity was somewhat lower (79% and 90%, respectively). CONCLUSIONS: Unstable detrusor contractions could be identified in infants by evaluation of radiological signs on voiding cystourethrography. Findings of bladder wall irregularity, elongation of bladder shape and filling of the posterior urethra indicated unstable detrusor contraction. The more such findings are observed, the stronger the indication.

Female↗
PubMed2001

Loss of heterozygosity and microsatellite instability at chromosomal sites 1Q and 10Q in morphologically distinct regions of late stage prostate lesions.

PURPOSE: We investigated the incidence of loss of heterozygosity (LOH) and microsatellite instability in sporadic prostate cancer and surrounding tissue at loci encompassing the HPC1 and PTEN genes. MATERIALS AND METHODS: Surgical specimens from 63 patients with sporadic stage T3 or T4 prostatic adenocarcinoma were analyzed for LOH and microsatellite instability. Microdissected tissue included morphologically normal foci, benign prostatic hyperplasia (BPH) and prostatic adenocarcinoma. LOH analysis was performed using 4 microsatellite markers that map in the region of the 1q24 to 25 locus of the putative prostate cancer susceptibility gene HPC1 and 4 that map in the region of the 10q23 locus of the PTEN gene. RESULTS: The incidence of LOH on 10q was consistent with that previously reported in prostatic tumors. LOH associated with the PTEN locus was recorded in morphologically normal foci, BPH and adenocarcinoma. Sequence analysis of PTEN in a limited number of lesions revealed mutations in nontumor and tumor tissue. Analysis of the DS10215 locus showed significant LOH in tumor but not in benign tissue, suggestive of a tumor suppressor gene in this region associated with prostatic neoplastic progression. In contrast, no significant LOH was observed in the same tissues at 4 loci on chromosome 1q. In this study we recorded elevated levels of microsatellite instability in benign prostatic tissue with an additional increase associated with prostatic adenocarcinoma. CONCLUSIONS: The low incidence of LOH in the region of the HPC1 locus in all prostate lesions studied suggests that this putative hereditary prostate cancer susceptibility locus does not appear to have a role in sporadic prostate cancer, at least not in the context of LOH. In contrast, analysis of the same tissues for LOH at chromosome 10q confirmed frequent alterations in this region linked to late stage prostate cancer. PTEN mutations in microdissected morphologically normal and BPH tissue showed alterations in nontumor tissue surrounding adenocarcinoma. Microsatellite instability was increased in adenocarcinomas over an elevated background recorded in surrounding tissues.

Adenocarcinoma↗
PubMed2001

The presence of single nucleotide instability in human breast cancer cell lines.

The presence of single nucleotide instability, an increase of spontaneous point mutation rates (MR: number of mutations per cell division) without microsatellite instability, was demonstrated previously in two rat mammary carcinoma cell lines. In this study, spontaneous point MRs were analyzed in human breast cancer cell lines by the fluctuation test using the hypoxanthine-guanine phosphoribosyltransferase (hprt) marker gene. MRs obtained for six breast cancer cell lines, MCF-7, ZR-75-1, T-47D, MDA-MB-231, MDA-MB-468, and BT-474, all of which were proficient in G/T mismatch binding and reported to be negative for microsatellite instability, were 7.6, 4.6, 6.3, 2.2, 5.6, and 19 x 10(-7) mutations/hprt/cell division. Those in normal human mammary epithelial cells and in a colon cancer cell line with proficient mismatch repair, SW480, were 1.6 and 1.4 x 10(-7) mutations/hprt/cell division, respectively. These findings showed that single nucleotide instability was also present in five of the six human breast cancer cell lines and strongly indicates it has important roles in human and rat mammary carcinogenesis.

Base Pair Mismatch↗
PubMedDate not supplied

HRAS1 minisatellite alleles in colorectal carcinoma: relationship to microsatelite instability.

OBJECTIVES: To further evaluate sporadic colon carcinoma risk associated with rare HRAS1 VNTR alleles, the relationship with microsatellite instability and with HRAS1 VNTR instability. MATERIALS AND METHODS: The HRAS1 VNTR was genotyped in 121 tumors and normal samples from sporadic colon carcinoma patients (47 right and 74 left colon) and in 109 samples from healthy individuals. The HRAS1 alleles were identified using PCR and automatic fluorescent electrophoresis detection combined with MVR-PCR (Minisatellite Variant Repeat-Polymerase Chain Reaction). Microsatellite Instability (MI) was analysed with 10 microsatellite markers. RESULTS: A relative risk of 3.04 (95% CI: 1.16-4.92) associated with rare alleles was obtained. No HRAS1 minisatellite instability was present in the tumors. Samples with MI were equally distributed between the common and rare HRAS1 allele groups, while the distribution of HRAS1 alleles in samples with MI was similar in right and left colorectal carcinoma. CONCLUSION: Rare HRAS1 VNTR alleles are associated with colorectal carcinoma risk independent of the tumor location. MI is not likely to be involved in the same underlying defect that generates rare HRAS1 alleles in colorectal carcinoma.

Adenocarcinoma↗
PubMed2001

Genomic instability in human lymphoid cells exposed to 1 GeV/amu Fe ions.

The goal of this study was to assess whether charged particle radiations of importance to spaceflight elicit genomic instability in human TK6 lymphoblasts. The incidence of genomic instability in TK6 cells was assessed ~21 days after exposure to 2, 4, or 6 Fe ions (1 GeV/amu, LET= 146 keV/micrometers). Three indices of instability were used: intraclonal karyotypic heterogeneity, mutation rate analysis at the thymidine kinase (TK1) locus, and re-cloning efficiency. Fifteen of sixty clones demonstrated karyotypic heterogeneity. Five clones had multiple indicators of karyotypic change. One clone was markedly hypomutable and polyploid. Six clones were hypomutable, while 21 clones were mutators. Of these, seven were karyotypically unstable. Six clones had low re-cloning efficiencies, one of which was a mutator. All had normal karyotypes. In summary, many clones that survived exposure to a low fluence of Fe ions manifested one or more forms of genomic instability that may hasten the development of neoplasia through deletion or by recombination.

Cell Line↗
PubMed2002

Evaluation of bladder instability in children with recurrent urinary tract infections.

BACKGROUND: Impairment in the functions of the lower urinary tract can be the cause of recurrent urinary tract infections (UTI) and vesicoureteral reflux (VUR) in children. The purpose of our research was to evaluate the frequency of occurrence of bladder instability in children with UTI. MATERIAL/METHODS: The research involved 114 children (21 boys, 93 girls), ranging in age from 5 to 16. Group I consisted of 61 children with a history of recurrent UTI, while Group II included 53 children with recurrent UTI and VUR. Urodynamic tests (uroflowmetry and cystometry) were done on all the children, while in selected cases profilometry was also performed, using a Duet apparatus (Dantec Medical A/S). RESULTS: Abnormal functioning of the lower urinary tract was found in 45 children (74%) from Group I and 44 children (84%) from Group II. The most common dysfunction was instability of the detrusor muscle, which was found in 52 children (45%), including 23 (38%) from Group I and 29 (55%) from Group II. In 19 children detrusor instability was accompanied by reduced bladder volume, and in 8 cases there was a lack of detrusor-sphincter coordination. In both groups ca. 20% of the children did not present with symptoms indicating urination dysfunctions. Ca. 80% reported various symptoms, of which the most common were nocturnal wetting and urinary urgency. In half of the children from Group I and one-fourth of the children from Group II there were several co-occurring symptoms: nocturnal and diurnal wetting, pollakiruria, and urinary urgency, or all three symptoms simultaneously. CONCLUSIONS: The most common disturbance of lower urinary tract functioning in these children with recurrent UTI was instability of the detrusor muscle, which occurred more often in children with VUR.

Adolescent↗
PubMed2002

Genomic instability at the human CD5 gene promoter.

BACKGROUND AND OBJECTIVES: The gene coding for the human CD5 lymphocyte surface receptor maps to the 11q12.2 region, which is in the vicinity of a region commonly affected by multiple somatic mutations in human cancers. The 5'-flanking region of the human CD5 gene includes an evolutionarily conserved (TC)n(CA)n microsatellite (MS) of potential utility as a marker for genome instability. The aim of the present study was to investigate the value of the CD5 MS as a marker for instability in different tumor types, particularly in B-cell leukemia and lymphoma. DESIGN AND METHODS: The CD5 MS and a panel of 10 MS markers were analyzed by using a polymerase chain reaction (PCR)-based method and polyacrylamide sequencing gels. This was done in several hematopoietic and non-hematopoietic cell lines, as well as in 28 cases of B-cell chronic lymphocytic leukemia (B-CLL), 19 mantle cell lymphomas (MCL) and 45 head and neck carcinomas (HNC). RESULTS: The frequency of CD5 MS abnormalities found among HNC was similar to that reported for other well known MS markers at loci near known and suspected cancer genes. However, instability at the CD5 MS was the most frequent MS abnormality among B-CLL and MCL. INTERPRETATION AND CONCLUSIONS: The inclusion of MS markers at chromosome 11q may be especially informative for genome instability analyses of certain B-cell leukemias and lymphomas.

CD5 Antigens↗
PubMed2002

Genetic instability in cancer tissues analyzed by random amplified polymorphic DNA PCR.

OBJECTIVE: To detect DNA and chromosomes instabilities during the progression of tumors and screen new molecular markers coupled to putative or unknown oncogenes and/or tumor suppressor genes. METHODS: Five kinds of tumors, in a total of 128 specimens, were analyzed by random amplified polymorphic DNA (RAPD) PCR. Bands representing instabilities were recovered, purified, and cloned, labeled as probes for Southern and Northern blot analysis and DNA sequencing. RESULTS: Sample 5 and 3 of the gastric cancer tissues showed the highest genomic changes and the average detectability in five cancers was up to at least 40% (42.2% - 49.4%). There were significant differences in the ability of each primer to detect genomic instability, which ranged from 27% (primer 8) to 68% (primer 2). Band B is a single copy fragment, and was found to be an allelic loss in gastric and colon cancers. It is a novel sequence and was registered in GenBank with Accession Number AF151005. Further analysis revealed that it might be part of a cis-regulatory element of a new tumor suppressor gene, containing a promoter of cis-action "CACA" box, an enhancer of "GATA" family and a start codon. CONCLUSIONS: It was impossible or difficult to get great achievements for cancer treatments with the procedure of gene therapy only to one oncogene or one tumor suppressor gene because the extensive DNA variations occurred during the progression of tumor. RAPD assay connected with other techniques was a good tool for the detection of genomic instabilities and direct screening of some new molecular markers related to tumor suppressor genes or oncogenes.

Base Sequence↗
PubMed1994

Marital instability in a rural population in south-west Uganda: implications for the spread of HIV-1 infection.

"The aim of this study was to examine people's beliefs about the causes of marital instability in a rural population cohort in south-west Uganda. Results from a baseline survey of HIV-1 infection in the cohort of over 4,000 adults (over 12 years old) showed a twofold increase in risk of infection in divorced or separated persons when compared with those who are married. A purposive sample of 134 respondents (seventy-two males, sixty-two females) selected to represent different ages, religions and marital status were asked in semi-structured interviews to comment on the reasons for continuing marital instability in their community. The most common reasons suggested for marital instability were sexual dissatisfaction, infertility, alcoholism and mobility....HIV infection was not mentioned as a direct cause of separation, but a small independent study revealed that seven out of ten couples separated on learning of a positive HIV test result of one or both partners. Marital instability is not uncommon in this population; there is evidence that HIV infection is making the situation worse." (SUMMARY IN FRE)

Africa↗
PubMed1976

Classification of knee ligament instabilities. Part I. The medial compartment and cruciate ligaments.

Based on the clinical and operative findings in sixty-eight knees with acute tears of the medial compartment and cruciate ligaments, a standardized terminology and classification of knee ligament instability is presented. With an intact posterior cruciate ligament, anteromedial, anterolateral, or posterolateral rotatory instability may occur, but not true posteromedial rotatory instability. With the posterior cruciate ligament ruptured, straight anterior, posterior, medial, or lateral instability may be found.

Humans↗
PubMed2003

Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review.

PURPOSE: To review studies of radiation responses in the haemopoietic system in the context of radiation-induced genomic instability, bystander effects and inflammatory-type processes. RESULTS: There is considerable evidence that cells that themselves are not exposed to ionizing radiation but are the progeny of cells irradiated many cell divisions previously may express a high frequency of gene mutations, chromosomal aberrations and cell death. These effects are collectively known as radiation-induced genomic instability. A second untargeted effect results in non-irradiated cells exhibiting responses typically associated with direct radiation exposure but occurs as a consequence of contact with irradiated cells or by receiving soluble signals from irradiated cells. These effects are collectively known as radiation-induced bystander effects. Reported effects include increases or decreases in damage-inducible and stress-related proteins; increases or decreases in reactive oxygen species, cell death or cell proliferation, and induction of mutations and chromosome aberrations. This array of responses is reminiscent of effects mediated by cytokines and other similar regulatory factors that may involve, but do not necessarily require, gap junction-mediated transfer, have multiple inducers and a variety of context-dependent consequences in different cell systems. That chromosomal instability in haemopoietic cells can be induced by an indirect bystander-type mechanism both in vitro and in vivo provides a potential link between these two untargeted effects and there are radiation responses in vivo consistent with the microenvironment contributing secondary cell damage as a consequence of an inflammatory-type response to radiation-induced injury. Intercellular signalling, production of cytokines and free radicals are features of inflammatory responses that have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. The induction of bystander effects and instabilities may reflect interrelated aspects of a non-specific inflammatory-type response to radiation-induced stress and injury and be involved in a variety of the pathological consequences of radiation exposures.

Animals↗
PubMed2003

Characterization of sporadic colon cancer by patterns of genomic instability.

Colorectal cancer (CRC) can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). We hypothesized that these two pathways are not always independent and that some tumors therefore show a significant degree of overlap between these two mechanisms. We classified 209 high-risk stage II and stage III sporadic CRCs based on their MSI status, using a National Cancer Institute-recommended panel of microsatellite markers, and also identified MSI-associated mutations of CRC target genes such as TGFbetaRII. Evidence for CIN was gathered by identifying loss of heterozygosity (LOH) events on chromosomal arms 1p, 2p, 3p, 5q, 17p, and 18q, which are regions harboring mismatch-repair and tumor-suppressor genes that are significant in CRC development. Results of all molecular markers tested were correlated with clinicopathological variables of the cohort, including treatment outcome. Of the 209 cases, 65% cancers were microsatellite stable, 21% were MSI-low, and 14% were MSI-high (MSI-H). Overall, 51% of the tumors had at least one LOH event, with most frequent chromosomal losses observed on 18q (72.5%), followed by 5q (22%), 17p (21%), and 3p (14%). Interestingly, we observed a significant degree of overlap between MSI and CIN pathways. Of 107 cancers with LOH events, 7 (6.5%) were also MSI-H, and of 30 cancers that were MSI-H, 7 (23.3%) also had one or more LOH events. We also found that 37.8% of microsatellite-stable cancers had no LOH events identified, thus comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. Our data suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways.

Aged↗
PubMedDate not supplied

BAT-26 microsatellite instability does not correlate with the loss of hMLH1 and hMSH2 protein expression in sporadic endometrial cancers.

Microsatellite instability (MSI) is detected in about 20-25% of endometrial cancers (ECs). Incidence of this alteration correlates with lack of expression of certain mismatch repair genes such as hMLH1 and hMSH2. Although assessment of several markers has been proposed for identification of microsatellite unstable tumours, BAT-26, a mononucleotide microsatellite repeat, has been shown to be highly efficient when used as a single marker. The aim of the study was to evaluate instability within BAT-26 and expression of hMLH1 and hMSH2 proteins in sporadic endometrial cancer as well as to correlate these findings with histopathologic and clinical characteristics of tumours. Samples of 88 (74 endometrioid and 14 non-endometrioid) ECs were investigated for instability within BAT-26 by means of PCR and expression of hMLH1 and hMSH2 proteins using immunohistochemistry. BAT-26 MIS was discovered in 23.9% of endometrial cancers. Incidence of MSI did not correlated with grade, stage or depth of invasion. BAT-26 MSI was more frequent in non-endometrioid compared to endometrioid tumours (35.7% vs. 21.6%, respectively), but the difference was not statistically significant. Lack of hMLH1 and hMSH2 protein expression was detected in 21.6 and 15.9% of ECs, respectively, and did not correlate with clinicopathologic features of tumours. Loss of both hMLH1 and hMSH2 protein expression was similar in BAT-26 stable and unstable cancers. All cases of non-endometrioid tumours with BAT-26 MSI were positive for hMLH1. We can conclude that BAT-26 used alone may not be a reliable marker for identification of sporadic ECs with microsatellite instability induced by deficient expression of hMLH1 and hMSH2.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Microsatellite instability and expression of DNA mismatch repair genes in malignant astrocytic tumors from adult and pediatric patients.

Microsatellite instability (MSI) is used as a molecular marker for defective DNA mismatch repair (MMR) genes. We report here alterations of MSI in 15 malignant astrocytomas (WHO grade III) and glioblastomas (GBM; WHO grade IV) of pediatric patients (2 - 21 years) and 12 GBM from adults (44 - 68 years) by comparative analysis of BAT25/BAT26 loci and 10 other microsatellite markers. High-level microsatellite instability (MSI-H) occurred in 4 of the 15 pediatric cases (26.7%) and in 1 of the 12 adult GBM cases (8.3%). Low-level microsatellite instability (MSI-L) was observed in 6 pediatric cases (40%) and 8 adult GBM (66.7%). Unstable BAT-25 locus was found in 1 of the MSI-H pediatric cases. Thus, 2 unstable cases showed no instability of this marker. For BAT-26, such a discordance was even more profound: in 1 of MSI-H cases, we obtained no PCR product and the remaining 3 showed no alterations of this marker. MSH2 (Human MutS, Homologue2) protein was detected in all but 3 pediatric cases (1 highly unstable and 2 low-level unstable) and in all adult cases. MLH1 (Human MutL, Homologue 1) protein was detected in all but 2 pediatric cases (1 highly unstable and 1 low-level unstable). Thus, 2 highly unstable pediatric cases showed no detectable MLH1/MSH2 proteins. Our data support earlier observations that MSI occurs predominantly in malignant astrocytic tumors of young patients, which lends support to the hypothesis of different molecular mechanisms of pediatric brain tumors. Surprisingly, we found no significant correlation between the status of 10 microsatellite markers and that of either BAT25 or BAT26 loci or with the expression of MMR genes.

Adaptor Proteins, Signal Transducing↗