Department of Dermatology, University of Utah School of Medicine, 30 N. 1900 E, Salt Lake City, UT 84132-2101, USA.
Breast Cancer Res. 2011 Jul 25;13(4):R73. doi: 10.1186/bcr2919.
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.
共济失调毛细血管扩张突变基因（ATM）（MIM ID 208900）编码一种蛋白激酶，在通过 DNA 损伤反应途径中的核心蛋白的后续磷酸化来激活细胞对 DNA 双链断裂的反应中起着重要作用。最近的研究证实，ATM 基因中的一些特定变体与乳腺癌（BC）风险增加有关。然而，风险的大小和导致乳腺癌的变体亚组仍未解决。
为了研究 ATM 在 BC 易感性中的作用，我们在 2570 例乳腺癌病例和 1448 例对照的病例对照家系研究中研究了 ATM 基因中的 76 个罕见序列变体。根据其可能的致病性，通过计算机分析将变体分为三类，并通过条件逻辑回归进行分析。对 27 个携带 c.7271T > G 携带者先证者的 129 个家族成员中的可能致病序列变体进行了基因分型，并使用修改的分离分析来估计与这些罕见 ATM 变体相关的 BC 外显率。
在病例对照分析中，我们观察到最有可能的有害变体的优势比为 2.55 和 95%置信区间（CI，0.54 至 12.0）。在基于家族的分析中，与这些变体相关的风险增加的最大似然估计值为风险比（HR）= 6.88（95%CI，2.33 至 20.3；P = 0.00008），这意味着到 80 岁时，BC 的累积风险为 60%。对携带可能致病性罕见序列变体的 18 例女性乳腺癌肿瘤的杂合性丢失（LOH）分析显示，ATM 变体的缺失没有一致的模式。
本研究的风险估计表明，携带致病性变体 ATM c.7271T > G 或截断突变的女性患乳腺癌的风险显著增加，其外显率似乎与 BRCA2 中种系突变所赋予的相似。
