Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer

Abstract

Biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene result in ataxia-telangiectasia (A-T). Studies on A-T families have shown that obligate female carriers have increased risk of developing breast cancer. Here we have evaluated the role of known Finnish ATM germ line mutations as possible breast cancer predisposing alleles outside A-T families by analyzing their prevalence in large cohorts of familial and unselected breast cancer cases. Of seven different alterations, two were observed in the studied breast cancer material. ATM 6903insA (causing protein truncation) was seen in 3/541 familial and 5/1124 unselected cases, but not among healthy population controls (0/1107). 7570G>C (Ala2524Pro) occurred in 1/541 familial and 2/1124 unselected cases compared with 1/1107 in controls. Additionally, 8734A>G (Arg2912Gly) associated previously with breast cancer susceptibility and suggested to be causative also for A-T was detected in 2/541 of familial cases, but not in unselected cases (0/1124) or controls (0/1107). In total, heterozygous ATM mutation carriers were observed in 6/541 familial [P = 0.006, odds ratio (OR) 12.4, 95% confidence interval (CI) 1.5-103.3) and 7/1124 unselected cases (P = 0.07, OR 6.9, 95% CI 0.9-56.4), compared with 1/1107 in controls, suggesting an apparent yet overall limited contribution to predisposition to cancer. The current results also provided evidence for founder effects in the geographical distribution of these mutations. Interestingly, results from functional analysis of the breast cancer-associated ATM mutations indicated that cancer susceptibility is not restricted to mutations with dominant-negative effect on kinase activity, displayed only by 7570G>C, whereas 8734A>G showed only a partial defect in the phosphorylation of ATM substrates, and 6903insA seemed to be a null allele.

Discovering moderate-risk breast cancer susceptibility genes

“…By now, two follow-up studies and a pooled analysis have confirmed these results [28][29][30]. Together, they revealed that: firstly, there are many ATM variants that confer a breast cancer risk, including essentially not only all truncating variants but also a variety of missense variants (Table 1); secondly, the prevalence of ATM variants varies widely among populations from different geographical areas or ethnicity; and thirdly, where investigated, most variants confer a breast cancer risk of about twofold.…”

A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer

“…In case of ATM, such common truncating mutations have been lacking, thus far, and the results presented in our study may help to fill a long-standing gap in this respect. Another recent study of an ATM frame-shift insertion in Finland, c.6903insA, has provided similar evidence for an association with breast cancer as this mutation was seen in 3/541 familial and 5/1,124 unselected Finnish cases, but not among 1,107 healthy population controls [27]. Supportive evidence has also been obtained for the possible association of an A-T causing missense mutation, c.7271T[G, with breast cancer [28].…”

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

“…Consistent with its role in genome stability maintenance, ATM is also an established tumour suppressor whose mutations or epigenetic silencing contributes to pathogenesis of a range of malignancies (Shiloh, 2003;Kastan and Bartek, 2004). Germline mutations of ATM predispose to familial breast cancer in a subset of families that do not carry mutations in either of the two prototypic breast cancerpredisposing genes, BRCA1 or BRCA2 (Renwick et al, 2006;Pylkas et al, 2007). In addition, defects of ATM, BRCA1 or BRCA2 also occur in some sporadic tumours (Turner et al, 2004;Prokopcova et al, 2007).…”