|
|||||
|
|
Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer |
|
| Authors: | Pylkäs Katri Tommiska Johanna Syrjäkoski Kirsi Kere Juha Gatei Magtouf Waddell Nicola Allinen Minna Karppinen Sanna-Maria Rapakko Katrin Kääriäinen Helena Aittomäki Kristiina Blomqvist Carl Mustonen Aki Holli Kaija Khanna Kum Kum Kallioniemi Olli-Pekka Nevanlinna Heli Winqvist Robert |
| Affiliation: | 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 |
| Abstract: | Biallelic mutations in the ataxia-telangiectasia mutated (ATM)gene result in ataxia-telangiectasia (A-T). Studies on A-T familieshave shown that obligate female carriers have increased riskof developing breast cancer. Here we have evaluated the roleof known Finnish ATM germ line mutations as possible breastcancer predisposing alleles outside A-T families by analyzingtheir prevalence in large cohorts of familial and unselectedbreast cancer cases. Of seven different alterations, two wereobserved in the studied breast cancer material. ATM 6903insA(causing protein truncation) was seen in 3/541 familial and5/1124 unselected cases, but not among healthy population controls(0/1107). 7570G>C (Ala2524Pro) occurred in 1/541 familialand 2/1124 unselected cases compared with 1/1107 in controls.Additionally, 8734A>G (Arg2912Gly) associated previouslywith breast cancer susceptibility and suggested to be causativealso for A-T was detected in 2/541 of familial cases, but notin 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)1.5103.3) and 7/1124 unselected cases (P = 0.07, OR 6.9,95% CI 0.956.4), compared with 1/1107 in controls, suggestingan apparent yet overall limited contribution to predispositionto cancer. The current results also provided evidence for foundereffects in the geographical distribution of these mutations.Interestingly, results from functional analysis of the breastcancer-associated ATM mutations indicated that cancer susceptibilityis not restricted to mutations with dominant-negative effecton kinase activity, displayed only by 7570G>C, whereas 8734A>Gshowed 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 |
| Keywords: | |
| 本文献已被 PubMed Oxford 等数据库收录！ | |