Chromosome Instability Syndromes

Cohen, Maimon M.; Levy, Howard P.

doi:10.1007/978-1-4613-0785-3_2

Cited by 60 publications

(21 citation statements)

References 482 publications

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“…Ataxia-telangiectasia (A-T) is an autosomal recessive disease expressed as cerebellar degeneration, telangiectasia, immune deficiency, chromosomal instability, increased tendency to lymphoreticular malignancies, and radiosensitivity (Boder 1985;Cohen and Levy 1989;McKinnon 1987). Cultured A-T cells show elevated chromosomal breakage and rearrangements, increased sensitivity to ionizing radiation and radiomimetic chemicals, and a decreased inhibition of DNA synthesis after treatment with these agents (McKinnon 1987;Shiloh et al 1985;Taylor 1982).…”

Section: Introductionmentioning

confidence: 95%

Ataxia-telangiectasia: Linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome

et al. 1992

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Ataxia-telangiectasia (A-T) is a progressive autosomal recessive disease featuring neurodegeneration, immunodeficiency, chromosomal instability, radiation sensitivity and a highly increased proneness to cancer. A-T is ethnically widespread and genetically heterogeneous, as indicated by the existence of four complementation groups in this disease. Several "A-T-like" genetic diseases share various clinical and cellular characteristics with A-T. By using linkage analysis to study North American and Turkish A-T families, the ATA (A-T, complementation group A) gene has been mapped to chromosome 11q23. A number of Israeli Arab A-T patients coming from large, highly inbred families were assigned to group A. In one of these families, an additional autosomal recessive disease was identified, characterized by ataxia, hypotonia, microcephaly and bilateral congenital cataracts. In two patients with this syndrome, normal levels of serum immunoglobulins and alpha-fetoprotein, chromosomal stability in peripheral blood lymphocytes and skin fibroblasts, and normal cellular response to treatments with X-rays and the radiomimetic drug neocarzinostatin indicated that this disease does not share, with A-T, any additional features other than ataxia. These tests also showed that another patient in this family, who is also mentally retarded, is affected with both disorders. This conclusion was further supported by linkage analysis with 11q23 markers. Lod scores between A-T and these markers, cumulated over three large Arab families, were significant and confirmed the localization of the ATA gene to 11q23. However, another Druze family unassigned to a specific complementation group, showed several recombinants between A-T and the same markers, leaving the localization of the A-T gene in this family open.

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Section: Introductionmentioning

confidence: 95%

Ataxia-telangiectasia: Linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome

et al. 1992

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“…These spontaneous rates are higher than those observed in other FA subgroups or in other chromosomal instability syndromes. 19 Further, these FA-D1 kindreds were not identified through the hematologic findings of aplastic anemia and bone marrow failure, but rather through a young child presenting with a solid tumor (medulloblastoma, Wilms tumor) who subsequently showed lethal sensitivity to chemotherapy. Each kindred later had a second affected child, one who developed a Wilms tumor followed by a medulloblastoma, and the other who developed T-lineage acute lymphoblastic leukemia (ALL).…”

Section: Introductionmentioning

confidence: 99%

Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood

Hirsch

Shimamura

Moreau

et al. 2004

Blood

173

111

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The clinical, cytogenetic, and molecular findings of 2 Fanconi anemia (FA) subtype D1 kindreds, initially identified through a young child with a solid tumor (medullobastoma, Wilms tumor), are described. Each kindred subsequently had a second affected child; one developed Wilms tumor followed by a medulloblastoma, and the other developed T-lineage acute lymphoblastic leukemia. Cytogenetic studies revealed an unusually high spontaneous chromosome aberration rate, contrasting with other FA subtypes. Molecular analysis revealed biallelic BRCA2/FANCD1 mutations. The patients did not exhibit bone marrow failure. Our studies suggest that the D1 subtype represents a severe end of the cytogenetic spectrum within FA, consistent with a critical downstream role of BRCA2 in the FA pathway. Furthermore, this FA subgroup may be preferentially associated with an increased predisposition to solid tumors in early childhood. Recognition of this constellation of findings has significant implications for medical management and genetic counseling of FA fami-

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“…The mechanisms of genetic instability in cancer cells are, therefore, of considerable interest. Chromosome instability in human cells may be caused by defects in various elements of DNA metabolism including replication, chromosome segregration, repair and recombination processes (Hartwell, 1992;Cohen and Levy 1989;Coquelle et al, 1997). Chromosomal aberrations and alterations in DNA ploidy can be induced by treatments with various drugs that damage DNA, including chemotherapeutic agents and chemical carcinogens, or by exposure to ionizing and ultraviolet radiations.…”

Section: Introductionmentioning

confidence: 99%

Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human fibroblasts expressing human papillomavirus type 16 E6 oncoprotein

et al. 1998

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Cell cycle checkpoints and tumor suppressor gene functions appear to be required for the maintenance of a stable genome in proliferating cells. In this study chromosomal destabilization was monitored in relation to telomere structure, lifespan control and G2 checkpoint function. Replicative senescence was inactivated in secondary cultures of human skin ®broblasts by expressing the human papillomavirus type 16 (HPV-16) E6 oncoprotein to inactivate p53. Chromosome aberrations were enumerated during in vitro aging of isogenic control (F5neo) and HPV-16E6-expressing (F5E6) ®broblasts. We found that structural and numerical aberrations in chromosomes were signi®cantly increased in F5E6 cells during aging in vitro and¯uorescence in situ hybridization (FISH) analysis using chromosome-speci®c probes demonstrated the occurrence of rearrangements involving chromosome 4 and 6 in genetically unstable F5E6 cells. Flow cytometry and karyotypic analyses revealed increased polyploidy and aneuploidy in F5E6 cells only at passages 416, although these cells displayed defective mitotic spindle checkpoint function associated with inactivation of p53 at passages 5 and 16. G2 checkpoint function was con®rmed to be gradually but progressively inactivated during in vitro aging of E6-expressing cells. Aging of F5neo ®broblasts was documented during in vitro passaging by induction of a senescence-associated marker, pH 6.0 lysosomal b-galactosidase. F5E6 cells displayed extension of in vitro lifespan and did not induce b-galactosidase at high passage. Erosion of telomeres during in vitro aging of telomerase-negative F5neo cells was demonstrated by Southern hybridization and by quantitative FISH analysis on an individual cell level. Telomeric signals diminished continuously as F5neo cells aged in vitro being reduced by 80% near the time of replicative senescence. Telomeric signals detected by FISH also decreased continuously during aging of telomerasenegative F5E6 cells, but telomeres appeared to be stabilized at passage 34 when telomerase was expressed. Chromosomal instability in E6-expressing cells was correlated (P50.05) with both loss of telomeric signals and inactivation of G2 checkpoint function. The results suggest that chromosomal stability depends upon a complex interaction among the systems of telomere length maintenance and cell cycle checkpoints.

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Chromosome Instability Syndromes

Cited by 60 publications

References 482 publications

Ataxia-telangiectasia: Linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome

Ataxia-telangiectasia: Linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome

Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood

Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human fibroblasts expressing human papillomavirus type 16 E6 oncoprotein

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