Homozygous or compound heterozygous germline mutations in the ATM
gene cause the autosomal recessive disorder ataxia-telangiectasia (A-T). This progressive neurological childhood disease is characterized by cerebellar degeneration, immunological defects, extreme sensitivity for ionising radiation and increased risk for cancers, particularly lymphomas [1
mutations identified in A-T families can be classified in three categories; truncating mutations, mutations that lead to some expression of mutant protein that lacks kinase activity and missense mutations with reduced kinase activity (http://chromium.liacs.nk/lovd/
Heterozygous pathogenic ATM
mutation carriers, ~0.5–1% of the general population, do not display the symptoms observed in A-T patients. Several epidemiological studies have consistently shown elevated rates of breast cancer among female blood relatives of patients with A-T [2
]. Thompson et al. have shown that the overall relative risk in carriers was 2.23 [95% confidence interval (CI) 1.16–4.28] compared to the general population and 4.95 (95% CI 1.9–12.9) in those younger that age 50. A large review showed that ATM
mutations are more frequent in breast cancer patients selected on the basis of a family history of breast cancer than in unselected patients [4
]. Besides pathogenic ATM
mutations, a large number of ATM
variants (common polymorphisms and unclassified variants) have been described, which were found in cancer patients as well as in the general population. It has been hypothesized that the cancer risk among ATM
heterozygotes might be related to mutation type, suggesting that particularly missense mutations are associated with an increased risk [5
]. However, two recent studies by Thompson et al. and Renwick et al. showed that pathogenic ATM
mutations that cause A-T are breast cancer susceptibility alleles [2
]. This argues against the hypothesis that missense rather that truncating are associated with breast cancer.
Women with breast cancer have in general a three to fourfold increased risk of developing a new primary cancer in the opposite breast [8
]. The contralateral breast cancer (CBC) risk might be explained by the same genetic and hormonal factors that caused the first breast cancer. Treatment related factors, e.g. radiotherapy for primary breast cancer, may also contribute to the development of cancer in the contralateral breast [9
] (our own data, manuscript under review).
To evaluate whether germline ATM missense variants are significantly associated with CBC risk (results regarding ATM truncating mutations are reported elsewhere) and whether treatment modifies this risk, we conducted a case-control study in which we assessed the ATM missense mutation spectrum and frequency in women who developed their first breast cancer before age 50, with and without a second primary breast cancer.