Ataxia-telangiectasia (A-T) is a multisystem recessive disease characterized clinically by cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, sensitivity to radiomimetic agents, and cancer predisposition. This pleiotropic disorder is caused by mutations in the ATM (mutated in A-T) gene, which is located in the human chromosomal region 11q22-q23. The ATM gene product is a member of a novel family of large proteins implicated in the regulation of the cell cycle and response to DNA damage. Heterozygosity for A-T was previously suggested to be associated with an increased risk of tumors, particularly female breast cancer. Because of loss of constitutional heterozygosity at 11q22-q23 is a frequent event in breast and other tumors, suggesting the presence of a tumor suppressor gene(s) in this region, we screened blood DNA samples from 88 unrelated breast cancer patients of Swedish cancer families for ATM mutations using single-strand conformation polymorphism analysis. All patients had a family history of tumors previously associated with A-T heterozygosity or homozygosity. We demonstrate the first three germ-line mutations in ATM identified by screening of breast cancer patients. Two mutations were previously found in A-T homozygotes and one mutation was a 1-bp insertion. All mutations were found in families with a large number of tumors, however, they did not cosegregate with malignancies. Although the proportion of A-T carriers in this sample seems to be higher than expected by chance, larger studies and pooled data sets will be required to establish that an A-T allele confers cancer susceptibility in heterozygotes.

ATM mutations in cancer families

NEGRINI, Massimo;CROCE, Carlo Maria;
1996

Abstract

Ataxia-telangiectasia (A-T) is a multisystem recessive disease characterized clinically by cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, sensitivity to radiomimetic agents, and cancer predisposition. This pleiotropic disorder is caused by mutations in the ATM (mutated in A-T) gene, which is located in the human chromosomal region 11q22-q23. The ATM gene product is a member of a novel family of large proteins implicated in the regulation of the cell cycle and response to DNA damage. Heterozygosity for A-T was previously suggested to be associated with an increased risk of tumors, particularly female breast cancer. Because of loss of constitutional heterozygosity at 11q22-q23 is a frequent event in breast and other tumors, suggesting the presence of a tumor suppressor gene(s) in this region, we screened blood DNA samples from 88 unrelated breast cancer patients of Swedish cancer families for ATM mutations using single-strand conformation polymorphism analysis. All patients had a family history of tumors previously associated with A-T heterozygosity or homozygosity. We demonstrate the first three germ-line mutations in ATM identified by screening of breast cancer patients. Two mutations were previously found in A-T homozygotes and one mutation was a 1-bp insertion. All mutations were found in families with a large number of tumors, however, they did not cosegregate with malignancies. Although the proportion of A-T carriers in this sample seems to be higher than expected by chance, larger studies and pooled data sets will be required to establish that an A-T allele confers cancer susceptibility in heterozygotes.
1996
Vorechovsky, I.; Luo, L.; Lindblom, A.; Negrini, Massimo; Webster, A. D. B.; Croce, Carlo Maria; Hammarstrom, L.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1206427
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