Comparative evaluation of diepoxybutane sensitivity and cell cycle blockage in the diagnosis of Fanconi anemia

Seyschab, Helga; Friedl, Richard; Sun, Yujie; Schindler, Detlev; Hoehn, Holger; Hentze, Sabine; Schroeder-Kurth, Traute

doi:10.1182/blood.v85.8.2233.bloodjournal8582233

Cited by 98 publications

(38 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another diagnostic technique with comparable accuracy to chromosome breakage studies is based on flow cytometric analysis of cells exposed to DNA cross‐linking agents to measure the prolonged progression through, and arrest within, the G2‐phase, which is characteristic of FA cells (Schindler et al , 1985; Berger et al , 1993; Seyschab et al , 1995). Such an approach has the advantage that it is less time‐consuming and does not require cytogenetic expertise and it may also sometimes be helpful when there are discrepancies on DEB testing (Toraldo et al , 1998).…”

Section: Diagnosis and Assessmentmentioning

confidence: 99%

Fanconi anaemia and leukaemia – clinical and molecular aspects

2004

View full text Add to dashboard Cite

Summary Fanconi anaemia (FA) is an autosomal recessive chromosomal instability disorder, which is characterized by congenital abnormalities, defective haemopoiesis and a high risk of developing acute myeloid leukaemia and certain solid tumours. It can be caused by mutations in at least eight different genes. Molecular studies have established that a common pathway exists, both between the FA proteins and other proteins involved in DNA damage repair such as NBS1, ATM, BRCA1 and BRCA2. This review summarizes the general clinical and specific haematological features and the current management of FA. Recent molecular advances will also be discussed in the context of the cellular and clinical FA phenotype, with particular emphasis on the haematological aspects of the condition.

show abstract

Section: Diagnosis and Assessmentmentioning

confidence: 99%

Fanconi anaemia and leukaemia – clinical and molecular aspects

2004

View full text Add to dashboard Cite

show abstract

“…Cell cultures from FA patients exhibit an increased rate of spontaneous or induced chromosomal breakage by cross-linking agents such as diepoxybutane (DEB) and mitomycin C (MMC). This test and cell cycle studies are the currently used diagnostically to differentiate FA from other congenital aplastic anemias (non-FA) and idiopathic aplastic anemias [3,4]. Recently, measurement of serum ␣-fetopro-tein (sAFP) was introduced as a simple, sensitive, and specific test in the diagnosis of FA [5].…”

Section: Introductionmentioning

confidence: 99%

Serum α‐fetoprotein level in Fanconi's anemia: Evaluation of 33 Turkish patients

et al. 2002

View full text Add to dashboard Cite

Recently, measurement of serum ␣-fetoprotein (sAFP) was introduced as a preliminary test for diagnosis of Fanconi's anemia (FA). In the present study, sAFP levels were measured in order to determine its sensitivity and specificity in 33 Turkish FA patients (17 males and 16 females) with a mean age of 11.6 ± 7.7 (1.0-28.0) (median 10.0). Complementation groups were available in 12 patients. Nineteen age-matched healthy children, 17 patients with bone marrow failure syndromes, 37 FA heterozygotes, and 37 children with acute leukemia served as negative control groups. The sAFP was measured by particle immunoassay. The level of sAFP was found to be higher than the cut-off value, 8 IU/mL in 46% and was within normal limits in 54% of the FA patients. The AFP values were within normal limits in all of the subjects belonging to the control groups. This method provided 46% sensitivity and 100% specificity in the diagnosis of FA. The sAFP values were high in 4 of 17 (24%) FA patients who did not receive any androgen therapy, while the sAFP level was high in 7 of 9 (78%) patients who received such a therapy. The statistical analysis of incidence of a high sAFP level between these two groups indicated a significant difference (P = 0.014), suggesting that androgen therapy might be a contributing factor for elevation of sAFP. The comparison of several clinical and laboratory parameters between FA patients with high and normal levels of AFP revealed no statistically significant differences. The level of sAFP was elevated in only 5 of the 11 patients with complementation group A; in addition, variable levels of sAFP were noted among the affected members in 4 families, indicating that complementation groups, type of mutation, or familial factors were not responsible for elevation of sAFP. Am. J. Hematol. 71:275-278, 2002.

show abstract

“…Resulting cell cycle distributions were quantified using the mplus av software package (Phoenix Flow Systems, San Diego, CA, USA) as previously described (Schindler & Hoehn, 1999). Cell cycle testing for G2-phase accumulations has been shown to arrive at the same diagnostic results as standard chromosome breakage analyses (Seyschab et al, 1995).…”

Section: Cell Cycle Analysismentioning

confidence: 99%

“…FANCJ as the BRCA1-interacting helicase BRIP1 has recently been identified by us and others (Levitus et al, 2005;Levran et al, 2005a) and might be involved in the stabilising role that has been described for BRCA1 in the ubiquitination of FANCD2 (Vandenberg et al, 2003). Defects within the FA pathway result in prolonged G2/M transition in the cell cycle (Dutrillaux et al, 1982;Seyschab et al, 1995) and defective DNA repair by homologous recombination (Venkitaraman, 2004). Exposure of FA cells to doses of DNA interstrand cross-linking agents tolerated by normal cells exhibits a characteristic cellular phenotype with complete G2/M arrest and cell death due to apoptosis.…”

mentioning

confidence: 97%

Delayed diagnosis and complications of Fanconi anaemia at advanced age – a paradigm

et al. 2006

View full text Add to dashboard Cite

SummaryFanconi anaemia (FA) is a rare recessive DNA repair disorder clinically characterised by congenital malformations, progressive bone marrow failure and a high propensity for developing malignancies at an early age, predominantly acute myeloid leukaemia (AML) and squamous cell carcinoma. It is conceivable that a number of patients with hypomorphic mutations are not diagnosed as FA until severe complications in the treatment of a malignancy occur. Here, we report on a patient with FA-A, diagnosed only at the age of 49 years due to persistent pancytopenia and myelodysplastic syndrome/AML induced by a first cycle of chemotherapy for bilateral metachronic breast cancer. This exceptional case clearly demonstrates that, in instances of long-lasting mild pancytopenia or development of malignancies, especially at an unusually young age, FA should be ruled out, irrespective of the patient's age and features, especially before inflicting severe genotoxic stress. . In the IFAR (Kutler et al, 2003), 10% of patients were diagnosed with one or more solid tumours, predominantly squamous cell carcinomas in the oro-pharyngeoesophageal and anogenital regions. Only three patients, however, were reported to have breast cancer. The risk of developing haematological and non-haematological malignancies amounted over time to a cumulative incidence of 33% and 28%, respectively, by 40 years of age. During the 20-year observation period, 38% of patients died at a median age of 24 years (Kutler et al, 2003). On a cellular level, FA is characterised by chromosomal instability and hypersensitivity to DNA interstrand crosslinking agents, such as mitomycin C (MMC), diepoxybutane (DEB) and cisplatin (D'Andrea & Grompe, 2003;Venkitaraman, 2003;Thompson et al, 2005). Complementation studies based on the correction of this hypersensitivity by somatic cell fusion have defined at least 12 complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, M) (Levitus et al, 2003). Eleven genes in which germline defects in patients result in the clinical phenotype of FA have been identified (FANCA, B, C, D1, D2, E, F, G, J, L, M) (Joenje & Arwert, 2001;Howlett et al, 2002;Levitus et al, 2005;Levran et al, 2005a;Meetei et al, 2005). Functional assays suggest that a core FA complex composed of the proteins FANCA, B, C, E, F, G, L and M as well as the FAassociated proteins FAAP100 (Meetei et al, 2003;Fei et al, 2005) activates FANCD2 by monoubiquitination (GarciaHiguera et al, 2001;Timmers et al, 2001). Monoubiquitinated FANCD2 protein, also referred to as FANCD2-L, then interacts with BRCA2/FANCD1 in chromatin (Hussain et al, 2004;Wang et al, 2004). FANCJ as the BRCA1-interacting helicase BRIP1 has recently been identified by us and others (Levitus et al, 2005;Levran et al, 2005a) and might be involved in the stabilising role that has been described for BRCA1 in the ubiquitination of FANCD2 (Vandenberg et al, 2003). Defects within the FA pathway result in prolonged G2/M transition in the cell cycle (Dutrillaux et al, 1982;Seyschab et al, 1995) and defectiv...

show abstract

Comparative evaluation of diepoxybutane sensitivity and cell cycle blockage in the diagnosis of Fanconi anemia

Cited by 98 publications

References 18 publications

Fanconi anaemia and leukaemia – clinical and molecular aspects

Fanconi anaemia and leukaemia – clinical and molecular aspects

Serum α‐fetoprotein level in Fanconi's anemia: Evaluation of 33 Turkish patients

Delayed diagnosis and complications of Fanconi anaemia at advanced age – a paradigm

Contact Info

Product

Resources

About