Heterozygous manifestations in four autosomal recessive human cancer-prone syndromes: ataxia telangiectasia, xeroderma pigmentosum, Fanconi anemia, and Bloom syndrome

Heim, Ruth A.; Lench, Nicholas; Swift, Michael

doi:10.1016/0027-5107(92)90022-t

Cited by 42 publications

(18 citation statements)

References 57 publications

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“…Whereas it was not completely unexpected that cells from FA patients themselves would show a distinctive behavior after exposure to ionizing radiation and subjection to the comet assay, no such behavior was or could be expected for cells from heterozygous individuals. Although obligate heterozygous individuals from FA families have not been extensively researched, all available evidence suggests that these individuals are free from major clinical symptoms, have a normal life expectancy, and only a minor, if any, elevation of cancer risk (Swift et al, 1980;Petridou and Barrett, 1990;Heim et al, 1992). To convince ourselves of the validity of our observations, we extended the group of heterozygous FA individuals from 10, initially, to a total of 34 donors.…”

Section: Discussionmentioning

confidence: 89%

Response to X-Irradiation of Fanconi Anemia Homozygous and Heterozygous Cells Assessed by the Single-Cell Gel Electrophoresis (Comet) Assay

Djuzenova

Rothfuß

Oppitz

et al. 2001

Laboratory Investigation

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SUMMARY:Fanconi anemia (FA) is an autosomal recessive disorder characterized by bone marrow failure and cancer susceptibility. Patient cells are sensitive to a variety of clastogens, most prominently cross-linking agents. Although there is the long-standing clinical impression of radiosensitivity, in vitro studies have yielded conflicting results. We exposed peripheral blood mononuclear cells from FA patients and carriers to x-rays and determined their DNA damage and repair profiles using the alkaline single-cell gel electrophoresis (comet) assay. Studies were carried out in two independent series of experiments by two laboratories using different protocols. The cells of both FA patients and carriers showed uniformly high initial DNA damage rates as assessed by the total initial tail moment. In addition, the average residual tail moment at 30 to 50 minutes and the repair half-time parameters were significantly elevated. These findings suggest an increased release of fragmented DNA following x-ray exposure in cells that carry one or two mutations in one of the FA genes. The comet assay may be a useful adjunct for heterozygote detection in families of FA patients. (Lab Invest 2001, 81:185-192).

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Section: Discussionmentioning

confidence: 89%

Response to X-Irradiation of Fanconi Anemia Homozygous and Heterozygous Cells Assessed by the Single-Cell Gel Electrophoresis (Comet) Assay

Djuzenova

Rothfuß

Oppitz

et al. 2001

Laboratory Investigation

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“…It remains unclear whether heterozygote carriers from other FA subtypes (non-D1 subtype) also have increased risk of breast, ovarian, or other cancers. 6,7 Third, ovarian tumors are often initially hypersensitive to cisplatinum but become cisplatinum resistant during treatment. Acquired cisplatin resistance is therefore an important problem in the clinical management of ovarian cancer patients.…”

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confidence: 99%

The Fanconi Anemia/BRCA Signaling Pathway: Disruption in Cisplatin-Sensitive Ovarian Cancers

D’Andrea¹

2003

Cell Cycle

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© 2 0 0 3 L a n d e s B i o s c i e n c e . N o t f o r d i s t r i b u t i o n . ABSTRACTOvarian tumors often exhibit chromosome instability and hypersensitivity to the chemotherapeutic agent cisplatin. Recently, we have shown that this cellular phenotype may result from an acquired disruption of the Fanconi Anemia/BRCA (FA/BRCA) signaling pathway. Disruption results from methylation and silencing of one of the FA genes (FANCF), leading to cisplatin sensitivity. Restoration of this pathway is associated with demethylation of FANCF, leading to acquired cisplatinum resistance. The serial inactivation and reactivation of the FA/BRCA pathway has important implications for the diagnosis and treatment of ovarian cancers and related cancers.

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“…AT can be regarded as an inherited cancer predisposition syndrome and there is evidence to suggest that the cancer predisposition extends to AT heterozygotes, although the magnitude and nature of the predisposition is controversial (Easton, 1994). The absence of clinical manifestation, and the lack of quantifiable in vitro cellular characteristics make identifying AT carriers in the general population unreliable (Heim et al, 1992;Scott et al, 1993;Bebb et al, 1998). Unfortunately, the size of the gene (150 Kb genomic, 13 Kb cDNA, 66 exons) and the lack of mutational hot spots makes screening approaches to mutation detection unwieldy to date (Savitsky et al, 1995;Gilad et al, 1996).…”

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confidence: 99%

Absence of mutations in the ATM gene in forty-seven cases of sporadic breast cancer

Bebb

Chen

et al. 1999

Br J Cancer

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Summary Epidemiological evidence points to an increased risk of breast cancer in ataxia telangiectasia (AT) heterozygote women. Previous attempts to screen early onset or familial breast cancer patients failed to confirm an association. The issue of AT and late onset sporadic breast cancer remained unresolved. We screened 47 women who developed later onset, sporadic breast cancer for ataxia telangiectasia mutated (ATM) mutations. No mutations were found.

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Heterozygous manifestations in four autosomal recessive human cancer-prone syndromes: ataxia telangiectasia, xeroderma pigmentosum, Fanconi anemia, and Bloom syndrome

Cited by 42 publications

References 57 publications

Response to X-Irradiation of Fanconi Anemia Homozygous and Heterozygous Cells Assessed by the Single-Cell Gel Electrophoresis (Comet) Assay

Response to X-Irradiation of Fanconi Anemia Homozygous and Heterozygous Cells Assessed by the Single-Cell Gel Electrophoresis (Comet) Assay

The Fanconi Anemia/BRCA Signaling Pathway: Disruption in Cisplatin-Sensitive Ovarian Cancers

Absence of mutations in the ATM gene in forty-seven cases of sporadic breast cancer

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