Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer

letterMice heterozygous for mutation in Atm, the gene

involved in ataxia-telangiectasia, have heightened

susceptibility to cancerKevin Spring1, Farida Ahangari1, Shaun P. Scott1, Paul Waring2, David M. Purdie1, Philip C. Chen1,

Kevin Hourigan3, Jonathan Ramsay1, Peter J. McKinnon4, Michael Swift5 & Martin F. Lavin1,6.com/naturegeneticsPublished online: 26 August, doi:10.1038/ng958Ataxia-telangiectasia is characterized by radiosensitivity,

genome instability and predisposition to cancer1,2. Heterozygous carriers of ATM, the gene defective in ataxia-telangiectasia, have a higher than normal risk of developing breast and

other cancers36. We demonstrate here that Atm knock-in

(Atm-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.

Missense mutations are the most common type of ataxia-telangiectasia mutations observed in individuals with breast cancer,

whereas truncating mutations are the most common type of

mutation observed in the total population of individuals affected

with ataxia-telangiectasia710. These findings indicate that different ATM mutations might differ in the degree of associated

excess cancer risk. To evaluate this possibility, we previously generated a mouse carrying a mutation that is common in people

with ataxia-telangiectasia (the 7636del9 deletion). These mice

carry a mutated Atm (Atmtm1Mfl, hereafter known as Atm-SRI)

that is functionally disrupted by an in-frame deletion of nine

nucleotides (7666del9), resulting in the loss of three amino acids.

The resulting mutant Atm protein is nearly full-length, but has

disrupted function11. The Atm-SRI homozygous mice developed thymic lymphomas and a variety of other tumors, but lived

longer than Atm/ mice1114. Here we monitored tumor formation in Atm-SRI heterozygous mice and compared it with

tumor incidence in Atm+/ and wildtype littermates