scholarly journals Cytogenetic diepoxybutane sensitivity in Serbian children with Fanconi anemia

2006 ◽  
Vol 58 (4) ◽  
pp. 215-219
Author(s):  
Sanja Cirkovic ◽  
Marija Guc-Scekic ◽  
Dragana Vujic ◽  
D. Micic
Keyword(s):  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Alkylating Agents ◽  
Chromosome Breakage ◽  
Child Health Care ◽  
Bone Marrow Failure Syndromes ◽  
Mother And Child Health ◽  
Mother And Child ◽  
And Child Health

Fanconi anemia (FA) is an inherited disorder with aplastic anemia, cancer susceptibility, and hypersensitivity to alkylating agents such as diepoxybutane (DEB). The DEB test is used to screen for FA among patients with bone marrow failure syndromes (BMFS). From February of 2004 to May of 2006, 29 children with BMFS were diagnosed and treated at the Mother and Child Health Care Institute of Serbia (MCHIS). In the examined group, five out of 29 patients (17.2%) were found to have increased DEB-induced chromosome breakage (0.58-2.15 vs. 0.00-0.20 breaks/cell; p<0.001) with no overlap. Our results suggest the importance of this analysis for differential diagnosis and adequate therapy of FA among patients with BMFS.

scholarly journals Chromosomal instability in patients with Fanconi anemia from Serbia

2014 ◽  
Vol 71 (4) ◽  
pp. 368-372
Author(s):  
Sanja Cirkovic ◽  
Marija Guc-Scekic ◽  
Dragana Vujic ◽  
Dragan Micic ◽  
Dejan Skoric
Keyword(s):  
Fanconi Anemia ◽  
Chromosomal Instability ◽  
Chromosome Breakage ◽  
Hereditary Disease ◽  
Child Health Care ◽  
Chemical Agents ◽  
Mother And Child Health ◽  
Mother And Child ◽  
Precise Diagnosis ◽  
And Child Health

Background/Aim. Fanconi anemia (FA) is a rare hereditary disease in a heterogeneous group of syndromes, so-called chromosome breakage disorders. Specific hypersensitivity of its cells to chemical agents, such as diepoxybutane (DEB), was used as a part of screening among patients with clinical suspicion of FA. The aim of this study was to determine chromosomal instability in patients with FA symptoms in Serbia. Methods. A total of 70 patients with phenotypic symptoms of FA, diagnosed at the Mother and Child Health Care Institute of Serbia ?Dr Vukan Cupic?, Belgrade and University Children?s Hospital, Belgrade from February 2004 to September 2011, were included in this study. Cytogenetic instability analysis was performed on untreated and DEBtreated 72 h-cultures of peripheral blood. Results. Ten patients in the group of 70 suspected of FA, showed increased DEB induced chromosome breakage and were classified into the FA group. The range of DEB induced aberrant cells percentages in the FA group was from 32% to 82%. DEB sensitivity of 58 tested patients were bellow FA values (range: 0-6%) (non-FA group), with no overlapping. The remaining two patients showed borderline sensitivity (borderline FA group - FA*), comparing to the healthy controls. Conclusion. This study revealed 10 patients with FA on the basis of cytogenetic analysis of DEB induced chromosome aberrations. Our results are in consistency with those from the literature. Early and precise diagnosis of FA is very important in further treatment of these patients, considering its cancer prone and lethal effects.

Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1329-1336 ◽  
Author(s):  
Jean Soulier ◽  
Thierry Leblanc ◽  
Jérôme Larghero ◽  
Hélène Dastot ◽  
Akiko Shimamura ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Somatic Mosaicism ◽  
Chromosome Breakage ◽  
Peripheral Blood Lymphocytes ◽  
Specific Analysis ◽  
Number Of Patients ◽  
Chromosome Fragility

AbstractFanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure, chromosome fragility, and cancer susceptibility. Eight FA-associated genes have been identified so far, the products of which function in the FA/BRCA pathway. A key event in the pathway is the monoubiquitination of the FANCD2 protein, which depends on a multiprotein FA core complex. In a number of patients, spontaneous genetic reversion can correct FA mutations, leading to somatic mosaicism. We analyzed the FA/BRCA pathway in 53 FA patients by FANCD2 immunoblots and chromosome breakage tests. Strikingly, FANCD2 monoubiquitination was detected in peripheral blood lymphocytes (PBLs) in 8 (15%) patients. FA reversion was further shown in these patients by comparison of primary fibro-blasts and PBLs. Reversion was associated with higher blood counts and clinical stability or improvement. Once constitutional FANCD2 patterns were determined, patients could be classified based on the level of FA/BRCA pathway disruption, as “FA core” (upstream inactivation; n = 47, 89%), FA-D2 (n = 4, 8%), and an unidentified downstream group (n = 2, 4%). FA-D2 and unidentified group patients were therefore relatively common, and they had more severe congenital phenotypes. These results show that specific analysis of the FA/BRCA pathway, combined with clinical and chromosome breakage data, allows a comprehensive characterization of FA patients.

scholarly journals Fanconi Anemia FANCG Protein in Mitigating Radiation- and Enzyme-Induced DNA Double-Strand Breaks by Homologous Recombination in Vertebrate Cells

2003 ◽  
Vol 23 (15) ◽  
pp. 5421-5430 ◽  
Author(s):  
Kazuhiko Yamamoto ◽  
Masamichi Ishiai ◽  
Nobuko Matsushita ◽  
Hiroshi Arakawa ◽  
Jane E. Lamerdin ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Chromosome Breakage ◽  
Breast Cancer Susceptibility ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Brca1 And Brca2 ◽  
Strand Breaks

ABSTRACT The rare hereditary disorder Fanconi anemia (FA) is characterized by progressive bone marrow failure, congenital skeletal abnormality, elevated susceptibility to cancer, and cellular hypersensitivity to DNA cross-linking chemicals and sometimes other DNA-damaging agents. Molecular cloning identified six causative genes (FANCA, -C, -D2, -E, -F, and -G) encoding a multiprotein complex whose precise biochemical function remains elusive. Recent studies implicate this complex in DNA damage responses that are linked to the breast cancer susceptibility proteins BRCA1 and BRCA2. Mutations in BRCA2, which participates in homologous recombination (HR), are the underlying cause in some FA patients. To elucidate the roles of FA genes in HR, we disrupted the FANCG/XRCC9 locus in the chicken B-cell line DT40. FANCG-deficient DT40 cells resemble mammalian fancg mutants in that they are sensitive to killing by cisplatin and mitomycin C (MMC) and exhibit increased MMC and radiation-induced chromosome breakage. We find that the repair of I-SceI-induced chromosomal double-strand breaks (DSBs) by HR is decreased ∼9-fold in fancg cells compared with the parental and FANCG-complemented cells. In addition, the efficiency of gene targeting is mildly decreased in FANCG-deficient cells, but depends on the specific locus. We conclude that FANCG is required for efficient HR-mediated repair of at least some types of DSBs.

scholarly journals The effect of the Fanconi anemia polypeptide, FAC, upon p53 induction and G2 checkpoint regulation

Blood ◽  
1996 ◽  
Vol 88 (3) ◽  
pp. 1019-1025 ◽  
Author(s):  
GM Kupfer ◽  
AD D'Andrea
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cell Lines ◽  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Alkylating Agents ◽  
P53 Pathway ◽  
G2 Checkpoint ◽  
G2 Phase

Fanconi anemia (FA) is an autosomal recessive disease marked by developmental defects, bone marrow failure, and cancer susceptibility. FA cells are hypersensitive to DNA cross-linking and alkylating agents and accumulate in the G2 phase of the cell cycle in response to these agents. FA cells also display genomic instability, suggesting a possible defect in the p53 pathway. To test the effect of heterologous expression of FAC cDNA on drug-induced cytotoxicity, G2 accumulation, and p53 induction in FA cells, we compared two isogenic FA cell lines: HSC536N (mock), a FA type C cell line sensitive to mitomycin C (MMC), and the same cell line transfected (corrected) with wild-type FAC cDNA (HSC536N [+FAC]). HSC536N (+FAC) cells showed a 30-fold increase in resistance to MMC concentration. Similarly, increases in resistance were observed following exposure to cisplatin, carboplatin, and cyclophosphamide. In addition, HSC536N (+FAC) cells showed a twofold lower G2 accumulation following MMC treatment. To analyze the possible interaction of FAC with the p53 pathway, we analyzed p53 induction in mock and corrected cell lines following exposure to MMC. HSC536N (mock) cells induced p53 at lower MMC concentrations than HSC536N (corrected). Caffeine, a known G2 checkpoint inhibitor, not only inhibited G2 accumulation seen in both cell lines but also caused the resistant HSC536N (+FAC) to become as sensitive to MMC as HSC536N (mock) cell line. We conclude that the FAC protein has a specific cytoprotective effect and may function as a cell cycle regulator of the G2 phase of the cell cycle.

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