The ATM gene and breast cancer: is it really a risk factor?

The genetic determinants for most breast cancer cases remain elusive. Whils t mutations in BRCA1' and BRCA2 significantly contribute to familial breast cancer risk, their contribution to sporadic breast cancer is low. Zn such cases genes frequently altered in the general population, such as the gene mutated in Ataxia telangiectasia(AT), ATM may be important risk factors. Th e initial interest in studying ATM heterozygosity in breast cancer arose fr om the findings of epidemiological studies of AT families in which AT heter ozygote women had an increased risk of breast cancer and estimations that 1 % of the population are AT heterozygotes. One of the clinical features of A T patients is extreme cellular sensitivity to ionising radiation. This obse rvation, together with the finding that a significant proportion of breast cancer patients show an exaggerated acute or late normal tissue reactions a fter radiotherapy, has lead to the suggestion that AT heterozygosity plays a role in radiosensitivity and breast cancer development. Loss of heterozyg osity in the region of the ATM gene on chromosome 11, has been found in abo ut 40% of sporadic breast tumours. However, screening for ATM mutations in sporadic breast cancer cases, showing or not adverse effects to radiotherap y, has not revealed the magnitude of involvement of the ATM gene expected. Their size and the use of the protein truncation test to identify mutations limit many of these studies. This latter parameter is critical as the prof ile of mutations in AT patients may not be representative of the ATM mutati ons in other diseases. The potential role of rare sequence variants within the ATM gene, sometimes reported as polymorphisms, also needs to be fully a ssessed in larger cohorts of breast cancer patients and controls in order t o determine whether they represent cancer and/or radiation sensitivity pred isposing mutations. (C) 2000 Elsevier Science B.V. All lights resented.