Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer
Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer
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DOI：
10.1093/carcin/bgl237
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发表时间：
2007-05-01
期刊：
影响因子：
4.7
通讯作者：
Winqvist, Robert
中科院分区：
文献类型：
--
作者：
Pylkas, Katri;Tommiska, Johanna;Winqvist, Robert
共济失调-毛细血管扩张突变（ATM）基因中的双等位基因突变导致共济失调-毛细血管扩张（A-T）。对A-T家族的研究表明，专性女性携带者患乳腺癌的风险增加。在这里，我们已经评估了已知的芬兰ATM种系突变的作用，可能是乳腺癌易感等位基因A-T家族以外的大队列的家族性和非家族性乳腺癌病例的患病率进行分析。在七种不同的改变中，在所研究的乳腺癌材料中观察到两种。ATM 6903 insA（导致蛋白质截短）见于3/541个家族性病例和5/1124个家族性病例，但未见于健康人群对照（0/1107）。7570 G> C（Ala 2524 Pro）基因型在家族性肝癌和非家族性肝癌中分别为1/541和2/1124，对照组为1/1107。此外，在2/541的家族性病例中检测到与乳腺癌易感性相关的8734 A> G（Arg 2912 Gly），并提示其也是A-T的病因，但在乳腺癌病例（0/1124）或对照（0/1107）中未检测到。总的来说，在6/541例家族性ATM突变携带者中观察到杂合子[P = 0.006，比值比（OR）12.4，95%置信区间（CI）1.5-103.3]，在7/1124例非家族性ATM突变携带者中观察到杂合子[P = 0.006，OR 12.4，95%置信区间（CI 1.5-103.3（P = 0.07，OR 6.9，95% CI 0.9-56.4），而对照组为1/1107，表明对癌症易感性的贡献明显但总体有限。目前的研究结果也为这些突变的地理分布中的奠基者效应提供了证据。有趣的是，乳腺癌相关ATM突变的功能分析结果表明，癌症易感性不限于对激酶活性具有显性负效应的突变，仅由7570 G> C显示，而8734 A> G仅显示ATM底物磷酸化的部分缺陷，6903 insA似乎是无效等位基因。
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.