Rare variants in the ATM gene and risk of breast cancer.
Rare variants in the ATM gene and risk of breast cancer.
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DOI：
10.1186/bcr2919
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发表时间：
2011-07-25
期刊：
影响因子：
--
通讯作者：
Chenevix-Trench G
中科院分区：
文献类型：
--
作者：
Goldgar DE;Healey S;Dowty JG;Da Silva L;Chen X;Spurdle AB;Terry MB;Daly MJ;Buys SM;Southey MC;Andrulis I;John EM;BCFR;kConFab;Khanna KK;Hopper JL;Oefner PJ;Lakhani S;Chenevix-Trench G
共济失调-毛细血管扩张症突变（ATM）基因（MIM ID 208900）编码一种蛋白激酶，该蛋白激酶在激活细胞对DNA双链断裂的反应中发挥重要作用，该反应通过随后DNA损伤反应途径中核心参与者的磷酸化来实现。最近的研究证实，ATM基因中的一些特定变异与乳腺癌（BC）风险增加有关。然而，风险的大小和乳腺癌致病性变异的子集仍然没有得到解决。为了研究ATM在乳腺癌易感性中的作用，我们在一项包括2,570例乳腺癌和1,448例对照的病例对照家族研究中研究了ATM基因中的76种罕见序列变异。根据其可能的致病性，将变体分为三类，如通过计算机模拟分析确定的，并通过条件logistic回归分析。对27名携带者先证者的129名家庭成员（其中15名携带c.7271T > G）进行可能致病的序列变异基因分型，并使用改良分离分析来估计与这些罕见ATM变异相关的BC突变率。在病例对照分析中，我们观察到最可能的有害变异的比值比为2.55和95%置信区间（CI，0.54至12.0）。在基于家族的分析中，与这些变异相关的风险增加的最大似然估计为风险比（HR）= 6.88（95%CI，2.33至20.3; P = 0.00008），相当于80岁时BC的累积风险为60%。对18例携带可能致病的罕见序列变异的女性乳腺肿瘤的杂合性缺失（洛）进行分析，发现ATM变异缺失的模式不一致。这项研究的风险估计表明，携带致病性变异ATM c.7271T > G或截短突变的女性患乳腺癌的风险显著增加，其突变率与BRCA 2生殖系突变相似。
The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved. To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants. In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant. The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2.
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