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Medline ® Abstract for Reference 21

of 'Ataxia-telangiectasia'

Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer.
Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, Hourigan K, Ramsay J, McKinnon PJ, Swift M, Lavin MF
Nat Genet. 2002;32(1):185. Epub 2002 Aug 26.
Ataxia-telangiectasia is characterized by radiosensitivity, genome instability and predisposition to cancer. Heterozygous carriers of ATM, the gene defective in ataxia-telangiectasia, have a higher than normal risk of developing breast and other cancers. We demonstrate here that Atm 'knock-in' (Atm-Delta SRI) heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation show an increased susceptibility to developing tumors. In contrast, no tumors are observed in Atm knockout (Atm(+/-)) heterozygous mice. In parallel, we report the appearance of tumors in 6 humans from 12 families who are heterozygous for the 7636del9 mutation. Expression of ATM cDNA containing the 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro. This reduces the survival of these cells after radiation exposure and enhances the level of radiation-induced chromosomal aberrations. These results show for the first time that mouse carriers of a mutated Atm that are capable of expressing Atm have a higher risk of cancer. This finding provides further support for cancer predisposition in human ataxia-telangiectasia carriers.
Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, 4029, Australia.