Sommer Steve S, Jiang Zefei, Feng Jinong, Buzin Carolyn H, Zheng Jian, Longmate Jeffrey, Jung Mira, Moulds Jefferson, Dritschilo Anatoly
Department of Molecular Genetics, City of Hope National Medical Center, Duarte, CA 91010-3000, USA.
Cancer Genet Cytogenet. 2003 Sep;145(2):115-20. doi: 10.1016/s0165-4608(03)00119-5.
Ataxia telangiectasia (A-T), an autosomal recessive neuro-immunologic disease with cancer susceptibility, results from ATM gene mutations. Most mutations in A-T patients cause protein truncation. Epidemiologic evidence suggests that ATM gene mutation carriers may be at increased risk for breast cancer, but the protein-truncating mutations that compose the majority of mutations in patients with ataxia telangiectasia are not elevated in women with breast cancer. In this report we present evidence that missense mutations in the ATM gene predispose to breast cancer. The analysis was performed in two phases in a total of 90 women with breast cancer and 90 ethnically similar control individuals. DOVAM-S, a robotically enhanced multiplexed, highly redundant form of SSCP in which virtually all mutations within the input amplicons can be detected, was used to scan all the coding exons and flanking splice junctions. Cohort-specific mutations were significantly elevated in women with breast cancer in phase 1 (43 cases) and phase 2 (47 cases). For the 90 patients and 90 controls, total missense mutations were significantly elevated in cases [OR=2.0; 90% CI=1.01-4.15]. Cohort-specific missense variants displayed an odds ratio of 4.0 (90% CI=1.37-13.5). It is estimated that the attributable risk of mutations in the ATM gene is 13% in this cohort of women with breast cancer.
共济失调毛细血管扩张症（A-T）是一种具有癌症易感性的常染色体隐性神经免疫疾病，由ATM基因突变引起。A-T患者中的大多数突变会导致蛋白质截短。流行病学证据表明，ATM基因突变携带者患乳腺癌的风险可能会增加，但在乳腺癌女性中，构成共济失调毛细血管扩张症患者大多数突变的蛋白质截短突变并未增加。在本报告中，我们提供证据表明，ATM基因中的错义突变易引发乳腺癌。分析分两个阶段对总共90名乳腺癌女性和90名种族相似的对照个体进行。DOVAM-S是一种通过机器人增强的多重、高度冗余的单链构象多态性形式，几乎可以检测输入扩增子内的所有突变，用于扫描所有编码外显子和侧翼剪接位点。在第一阶段（43例）和第二阶段（47例）的乳腺癌女性中，特定队列的突变显著增加。对于90名患者和90名对照，病例组中的总错义突变显著增加[比值比=2.0；90%置信区间=1.01-4.15]。特定队列的错义变异显示比值比为4.0（90%置信区间=1.37-13.5）。据估计，在这组乳腺癌女性中，ATM基因突变的归因风险为13%。
