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1/23. The hPMS2 exon 5 mutation and malignant glioma. Case report.

    patients with Turcot syndrome (TS) are predisposed to colon tumors and primary brain tumors, typically glioblastomas or medulloblastomas. The authors describe a patient with TS featuring a known germline mutation of exon 5 of the hPMS2 mismatch repair gene who developed two metachronous glioblastomas, both with distinct oligodendroglial features. Molecular genetic analysis revealed allelic loss of chromosome 19q in the patient's second tumor but no allelic loss of chromosome 1p. Prominent microsatellite instability was also found in this tumor, consistent with a germline mismatch repair defect. Because this patient had an unusual underlying condition and his tumor had a unique histological appearance for TS, it was hypothesized that this genetic defect may predispose to malignant gliomas with oligodendroglial features. The authors therefore evaluated whether sporadic glioblastomas and oligodendrogliomas undergo mutations of this region of the hPMS2 gene. However, single-strand conformation polymorphism analysis of hPMS2 exon 5 failed to reveal mutations in 20 sporadic glioblastomas and 16 sporadic oligodendroglial gliomas. Thus, although it is possible that the germline hPMS2 exon 5 mutation may predispose to glioblastomas with an oligodendroglial component, the same genetic defect is not commonly involved in sporadic oligodendrogliomas or glioblastomas.
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ranking = 1
keywords = microsatellite instability, microsatellite, instability
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2/23. Genetic instability did not lead to p53 mutations in an extremely early-onset breast cancer in a cancer-prone family.

    BACKGROUND: A positive family history is a major contributor to risk of development of breast cancer. methods: Somatic and germ line mutations of p53 and genetic instability were evaluated for an extremely early-onset breast cancer case in a cancer-prone family. RESULTS: The mode of inheritance in this case was clearly autosomal dominant. dna replication error was recognized by detecting microsatellite allelic alterations. However, mutations of p53 were not found at either somatic or germ-line level. CONCLUSION: These genetic studies suggest that an increased genetic instability did not lead to p53 gene mutations in this breast cancer patient.
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ranking = 0.27085470132224
keywords = microsatellite, instability
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3/23. Molecular basis and enzymatic properties of glucose 6-phosphate dehydrogenase volendam, leading to chronic nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections.

    We have investigated the blood cells from a woman with a low degree of chronic nonspherocytic hemolytic anemia and frequent bacterial infections accompanied by icterus and anemia. The activity of glucose 6-phosphate dehydrogenase (G6PD) in her red blood cells (RBCs) was below detection level, and in her leukocytes less than 3% of normal. In cultured skin fibroblasts, G6PD activity was approximately 15% of normal, with 4- to 5-fold increased Michaelis constant (Km) for nadp and for glucose 6-phosphate. Activated neutrophils showed a decreased respiratory burst. family studies showed normal G6PD activity in the RBCs from all family members, including both parents and the 2 daughters of the patient. Sequencing of polymerase chain reaction (PCR)-amplified genomic DNA showed a novel, heterozygous 514C-->T mutation, predicting a Pro172-->Ser replacement. Analysis of G6PD rna from the patient's leukocytes and fibroblasts showed only transcripts with the 514C-->T mutation. This was explained by the pattern of X-chromosome inactivation, studied by means of the human androgen receptor (HUMARA) assay, which proved to be skewed in the patient, her mother, and one of the patient's daughters. Thus, the patient has inherited a de novo mutation in G6PD from her father and an X-chromosome inactivation determinant from her mother, causing exclusive expression of the mutated G6PD allele. Purified mutant protein from an escherichia coli expression system showed strongly decreased specific activity, increased Km for nadp and for glucose 6-phosphate, and increased heat lability, which indicates that the defective phenotype is due to 2 synergistic molecular dysfunctions: decreased catalytic efficiency and protein instability.
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ranking = 0.0055842325833978
keywords = instability
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4/23. nijmegen breakage syndrome. The International nijmegen breakage syndrome Study Group.

    BACKGROUND: nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder. NBS-1, the gene defective in NBS, is located on chromosome 8q21 and has recently been cloned. The gene product, nibrin, is a novel protein, which is member of the hMre11/hRad50 protein complex, suggesting that the gene is involved in DNA double strand break repair. AIMS: To study the clinical and laboratory features of NBS as well as the genotype-phenotype relation. methods: Fifty five patients with NBS, included in the NBS registry in Nijmegen were evaluated. The majority of the patients were of eastern European ancestry. Most of them had shown a truncating 5 bp deletion 657-661 delACAAA. Four further truncating mutations have been identified in patients with other distinct haplotypes. RESULTS AND CONCLUSIONS: Essential features found in NBS were microcephaly, usually without severe retardation, typical facial appearance, immunodeficiency, chromosomal instability, x ray hypersensitivity, and predisposition to malignancy. In 40% of the patients cancer was noted before the age of 21 years. Important additional features were skin abnormalities, particularly cafe au lait spots and vitiligo, and congenital malformations, particularly clinodactyly and syndactyly. Congenital malformations, immunodeficiency, radiation hypersensitivity, and cancer predisposition were comprehensible in case of dysfunctioning of dna repair mechanisms. No specific genotype-phenotype relation could be found. patients with the same genotype may show different phenotypes and patients with different genotypes may express the same phenotype. Specific mutations did not lead to specific clinical features.
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ranking = 0.0055842325833978
keywords = instability
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5/23. Refined localization of autosomal recessive nonsyndromic deafness DFNB10 locus using 34 novel microsatellite markers, genomic structure, and exclusion of six known genes in the region.

    An autosomal recessive nonsyndromic deafness locus, DFNB10, was previously localized to a 12-cM region near the telomere of chromosome 21 (21q22.3). This locus was discovered in a large, consanguineous Palestinian family. We have identified and ordered a total of 50 polymorphic microsatellite markers in 21q22.3, comprising 16 published and 34 new markers, precisely mapped and ordered on BAC/cosmid contigs. Using these microsatellite markers, the locus for DFNB10 has been refined to an area of less than 1 Mb between markers 1016E7.CA60 and 1151C12.GT45. Six previously published cDNAs were mapped to this critical region, and their genomic structures were determined to facilitate mutation analysis in DFNB10. All six genes in this region (in order from centromere to telomere: White/ABCG1, TFF3, TFF2, TFF1, PDE9A, and NDUVF3) have been screened and eliminated as candidates for DFNB10. The new microsatellite markers and single nucleotide polymorphisms identified in this study should enable the refined mapping of other genetic diseases that map to 21q22.3. In addition, the critical region for DFNB10 has been reduced to a size amenable to an intensive positional cloning effort.
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ranking = 1.6614451407529
keywords = microsatellite
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6/23. Variegated aneuploidy related to premature centromere division (PCD) is expressed in vivo and is a cancer-prone disease.

    We present three patients with variegated aneuploidy and premature centromere division (PCD), a rare chromosomal abnormality in humans. Comparison of these three and eight other patients with variegated aneuploidy related to PCD demonstrates a phenotype comprising most frequently microcephaly, CNS anomalies (with cerebellar affection and migration defects), mental retardation, pre-and postnatal growth retardation, flat and broad nasal bridge, apparently low-set ears, eye and skin abnormalities, and ambiguous genitalia in male patients. The occurrence of wilms tumor in three patients, rhabdomyosarcoma in two others and acute leukemia in a fifth characterizes this condition as a chromosome or genome instability disorder with a high risk of malignancy. FISH studies in uncultured blood and buccal smear cells demonstrate that the random aneuploidies are not limited to cultured cells, but also occur in vivo.
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ranking = 0.0055842325833978
keywords = instability
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7/23. Familial nasal NK/T-cell lymphoma and pesticide use.

    Familial occurrence of nasal NK/T-cell lymphoma (NNKTCL) in pesticide users is presented. The proband (71 years old, male) and son (39 years old) were both diagnosed with NNKTCL within interval of 26 months. Laboratory data showed slight anemia, with no abnormal cells in peripheral blood. They and their wives were farmers and used large amounts of pesticides (fungicides and insecticides) in the hothouse. NNKTCL did not develop in the wives. Proband's father was diagnosed with malignant lymphoma of the neck and died of the disease. Genetic analyses of the peripheral blood leukocytes and tumor tissues did not show p53 and k-ras gene mutations and microsatellite instability. metaphase cells from peripheral blood leukocytes bore specific marker chromosomes (father, 44XY,-14,-17,-18,-22, 2mar; son, 46XY,-17, 1mar). Environmental exposures to pesticides in conjunction with familial or genetic factors might increase the risk for NNKTCL.
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ranking = 1
keywords = microsatellite instability, microsatellite, instability
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8/23. A genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q.

    Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. In this present study, we undertook a 10 cM genome screen using 400 microsatellite markers in a large multigenerational bipolar pedigree consisting of 40 individuals, including six affecteds. We found strongest evidence for linkage to chromosome 13q14. A maximum NPL score of 4.09 (P = 0.008) was obtained between markers D13S1272 and D13S153 using GENEHUNTER. A maximum two-point lod score of 2.91 (theta = 0.0) was found for marker D13S153 and a maximum three-point lod score of 3.0 was obtained between markers D13S291 and D13S153 under a recessive model with 90% maximum age-specific penetrance and including bipolar I and unipolar individuals as affected. Several other markers in the region, D13S175, D13S218, D13S263, and D13S156 had two-point LOD scores greater than 1.5. These results meet the criteria for evidence of suggestive linkage. Haplotype analysis enabled us to narrow the likely disease region to a 6 cM region between markers D13S1272 and D13S1319, which contains the serotonin 2A receptor candidate gene. Two single nucleotide polymorphisms were identified in this gene but we did not detect any significant differences in allele frequency in a case-control sample. The region on chromosome 13q14-32 has previously been implicated in other bipolar and schizophrenia cohorts. Our results provide further support for the existence of a susceptibility locus on chromosome 13q14.
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ranking = 0.23734930582185
keywords = microsatellite
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9/23. Extended genetic alterations in a patient with pulmonary sarcoidosis, a benign disease.

    BACKGROUND: Genetic alterations at the microsatellite level have been detected in various human malignant tissues, but have also been found in chronically inflamed tissues. sarcoidosis is a benign disease of unknown etiology characterized by chronic inflammation, which may be associated with an increased incidence of developing malignancy. methods: We examined the microsatellite alterations in a sputum cytological specimen of a patient with sarcoidosis. The DNA electrophoretic pattern of sputum was compared with that of the peripheral blood. Thirty-two microsatellite markers located at chromosomes 2p, 3p, 8p, 9p, 9q, 17p, 17q were used to reveal genetic alterations. RESULTS: loss of heterozygosity (LOH) was detected in eleven markers in loci 2p, 9p, 9q and 17q. LOH was observed in all four markers spanning the chromosomal arm 17q11.2-q21, suggesting a potential chromosomal deletion. CONCLUSION: The observation of LOH in all four markers spanning the chromosomal arm 17q11.2-q21 may suggest a potential for malignancy development in this patient, or may be linked to the aetiopathogenesis of sarcoidosis. Further microsatellite fine mapping and clinical follow up of this patient are needed to clarify this.
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ranking = 0.94939722328739
keywords = microsatellite
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10/23. genome instability in secondary solid tumors developing after radiotherapy of bilateral retinoblastoma.

    genome alterations of seven secondary tumors (five osteosarcomas, one malignant peripheral sheath nerve tumor, one leiomyosarcoma) occurring in the field of irradiation of patients treated for bilateral retinoblastoma have been studied. These patients were predisposed to develop radiation-induced tumors because of the presence of a germ line mutation in the retinoblastoma gene (RB1). Tumor cells were characterized by a high chromosome instability whereas microsatellites and minisatellites were found to be stable. In all tumors, the normal RB1 allele was lost with the corresponding chromosome 13, whereas the germ line mutated allele was retained. The two alleles of TP53 were inactivated, one by deletion of the short arm of chromosome 17, the other by mutation. As compared with non-radiation-induced tumors, the observed panel of TP53 mutations was uncommon with sites not recurrently found otherwise and a high rate of deletions (3/7). In these predisposed patients, the loss of the single normal allele of RB1 is rather due to the radiation-induced chromosome instability than a direct effect of ionizing radiation.
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ranking = 0.27085470132224
keywords = microsatellite, instability
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