The ATM gene and breast cancer: is it really a risk factor?
Section snippets
The ATM gene and breast cancer
Breast cancer is one of the most common malignancies in the world affecting 1 in ten women in the United Kingdom and one in nine in the United States. Linkage analysis of certain families with a high risk of breast cancer has identified two important susceptibility genes, BRCA1 and BRCA2, on chromosome 17q21 and 13q12–13, respectively [1]. However, epidemiological studies have shown that mutations in these genes are relatively rare in the general population and each is likely to account for
The ATM protein
Since the cloning of the ATM gene in 1995 [15], both its physiological role and its role in the cellular response to DNA damage have been extensively studied. The gene located on chromosome 11q23, is composed of 66 exons and codes for a 13-kb mRNA [16]. The ATM protein has a molecular mass of 350.6 kDa and is related to a family of yeast and mammalian proteins containing a phosphatidylinositol 3′-kinase domain with protein kinase activity 17, 18. These proteins are all involved in some aspect
ATM mutations
The profile of ATM mutations in AT children has revealed that most are unique and uniformly distributed along the length of the ATM gene. Most AT patients are compound heterozygotes having two different ATM mutations and patients homozygous for the same ATM mutation are rare [39]. The predominant type of mutation found in the ATM gene of AT patients with the “classical” form of the disease results in a truncated and unstable ATM protein easily detected using the protein truncation test [PTT] 45
Intrinsic radiosensitivity in breast cancer and the involvement of the ATM gene
Epidemiological studies have shown that irradiation of the breast especially among young women, increases the risk of subsequently developing breast cancer (reviewed in detail in Ref. [52]). It might thus be expected that genes that are known to influence radiation sensitivity and which are associated with an increased breast cancer risk, will be responsible for a proportion of such cases.
A significant proportion of breast cancer patients show an exaggerated acute or late reaction of normal
ATM status in breast tumours
The role of ATM as a risk factor for breast cancer is supported from the studies which have examined its status and expression in breast tumours. In many sporadic breast tumours, loss of heterozygosity has been frequently detected in the region of the ATM gene on chromosome 11q22–23 65, 66, 67, 68, 69, 70. In one recent study, Izatt et al. [71]reported that in five out of seven tumours with rare germline missense variants in the ATM gene, LOH of the wild-type ATM allele for one or more markers
Germline ATM alterations in breast cancer patients — AT family studies
Although, heterozygous carriers of the ATM gene show none of the neurological features of AT, there is consistent evidence that they have a higher risk of cancer in adulthood. A number of studies have shown that the female relatives of AT patients are at increased risk of breast cancer (see Table 1). Easton [10]undertook a pooled analysis of cancer risks in the studies published prior to the cloning of the ATM gene and estimated the relative risk of breast cancer to AT heterozygotes as 3.9-fold
Germline ATM alterations in sporadic breast cancer patients — the published mutational studies — problems and conflicts
The results published to date on the molecular characterisation of the ATM gene in sporadic breast cancer patients have produced conflicting results (Table 2). These studies have not revealed the magnitude of involvement that would have been expected from the increased risk found in the AT family studies and the frequency of AT heterozygotes in the population. The choice of the technique used to screen for ATM mutations and the cohort of breast cancer patients being studied could be
Conclusions
The connection between AT heterozygosity and sporadic breast cancer remains unresolved. The emerging picture does lend support to Gatti's observation at the recent 8th International workshop on AT that there seems to be two groups of AT heterozygotes in the general population. One group who are heterozygous for a truncating allele and a second group heterozygous for a missense mutation and that the latter group might predominantly include those individuals who are predisposed to developing
Acknowledgements
We would like to dedicate this paper to Ruggero Montesano on the occasion of his retirement with all our thanks for his continued support, encouragement, and guidance over the time we have spent in the Unit of Mechanisms of Carcinogenesis at the International Agency for Research on Cancer. Work in the laboratory is partly supported by grants from Association pour la Recherche sur le Cancer and La Ligue Nationale Contre le Cancer, Comité Départemental du Rhône.
References (100)
- et al.
ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer
Am. J. Hum. Genet.
(1998) - et al.
Ataxia telangiectasia — identification and detection of founder-effect mutations on the ATM gene in ethnic populations
Am. J. Hum. Genet.
(1998) - et al.
Genomic organisation of the ATM gene
Genomics
(1996) ATM: the product of the gene mutated in ataxia-telangiectasia
Int. J. Biochem. Cell Biol.
(1999)- et al.
A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia
Cell
(1992) - et al.
ATM-dependant interactions of a mammalian Chk1 homolog with meiotic chromosomes
Curr. Biol.
(1997) - et al.
Radiation-induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl
J. Biol. Chem.
(1999) - et al.
Ataxia-telangiectasia, mutations in ATM cDNA detected by protein truncation screening
Am. J. Hum. Genet.
(1998) - et al.
Leukemia and lymphoma in ataxia telangiectasia
Blood
(1996) - et al.
Inactivation of the ATM gene in T-cell prolymphocytic leukemias
Blood
(1998)