Carcinogenesis Advance Access originally published online on December 13, 2006
Carcinogenesis 2007 28(5):1040-1045; doi:10.1093/carcin/bgl237
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Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer
Department of Clinical Genetics, University of Oulu/Oulu University Hospital, FIN-90029 OYS Oulu, Finland
1 Department of Obstetrics and Gynecology
2 Department of Clinical Genetics
3 Department of Oncology, Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS Finland
4 Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere/Tampere University Hospital, Tampere, Finland
5 Department of Medical Genetics, University of Helsinki, Biomedicum Helsinki, Finland
6 Department of Biosciences at Novum and Clinical Research Centre, Karolinska Institutet, Huddinge, Sweden
7 Signal Transduction Laboratory, Queensland Institute for Medical Research, Herston, Qld, Australia
8 Department of Medical Genetics, University of Turku, Turku, Finland
9 Medical School, University of Tampere, and Palliative Unit, Tampere University Hospital, Tampere, Finland
10 Present address: Medical Biotechnology Unit, VTT Technical Research Centre of Finland and University of Turku, Turku, Finland
* To whom correspondence should be addressed. Tel: +358 8 3153228; Fax: +358 8 3153243; Email: robert.winqvist{at}oulu.fi
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.
Abbreviations: AI, allelic imbalance; A-T, ataxia-telangiectasia; ATM, ataxia-telangiectasia mutated; CI, confidence interval; IR, ionizing radiation; LCL, lymphoblast cell line; OR, odds ratio
Joint first authorship. Received October 11, 2006; revised November 23, 2006; accepted November 24, 2006.