The role of the ATM gene in familial breast cancer

描述(申请人提供)：ATM基因在乳腺癌易感性中的作用是有争议的。对ATM突变携带者的研究表明，女性患乳腺癌的风险平均增加4-7倍，但对未选定的乳腺癌病例的ATM基因突变分析未能发现与对照组相比令人信服的增加频率。然而，我们已经证明，ATM基因的两个特定的致病突变确实发生在4%的多发性乳腺癌家族中，并赋予乳腺癌的高风险，相当于70岁的风险60%。这项建议的主要目的是通过分析来自北美和澳大利亚的近3000个假定的遗传性乳腺癌家族的基因，估计导致乳腺癌的ATM突变的外显率和频率，从而扩大我们的发现。我们的具体目标是：1)对900个乳腺癌家系中最年轻的患病女性进行ATM突变筛查。2)通过对携带这些突变的妇女的肿瘤和细胞系中这些变异的行为进行分析，在这些变异中确定可能的ATM突变。3)对另外2000个乳腺癌家系进行AIM 2)中定义的假定ATM突变的筛查。4)对那些被发现携带假定ATM突变的个体的受影响和未受影响的家庭成员进行基因分型，并估计这些突变的外显率。5)估计未经选择的人群乳腺癌病例中ATM突变的频率。我们的发现将具有许多临床意义，包括是否应该对高危家庭中的女性进行常规或选择性的ATM筛查，以及BRCA1和BRCA2突变。此外，对ATM突变情况的了解将使今后能够对许多临床问题进行评估，包括外显性的遗传和环境修饰物、适当的监测、疾病的严重性、患者对不同治疗方案的反应以及放射治疗可能的不良反应。这项研究的结果可能直接影响治疗决策，并改善高危家庭的预防性监测。

DESCRIPTION (provided by applicant): The role of the ATM gene in breast cancer predisposition is controversial. Studies of carriers of ATM mutations have indicated that females have on average a 4-7 fold increased risk of breast cancer, but mutation analysis of the ATM gene in unselected breast cancer cases has failed to find a convincingly increased frequency compared with controls. However, we have shown that two specific pathogenic mutations of the ATM gene do occur in 4% of multiple-case breast cancer families, and confer high risks of breast cancer, equivalent to a risk to age 70 years of 60%. The broad aim of this proposal is to extend our finding by estimating the penetrance and frequency of breast cancer-causing ATM mutations by analysis of the gene in almost 3000 putative hereditary breast cancer families from North America and Australia. Our specific aims are to: 1) Perform mutation screening of ATM in the youngest affected female from 900 breast cancer families. 2) Identify putative ATM mutations among the variants found by analyses of the behaviour of these variants in tumors and cell lines from women who carry them. 3) Screen 2000 additional breast cancer families for putative ATM mutations defined in Aim 2. 4) Genotype the affected and unaffected family members of those individuals found to carry putative ATM mutations, and estimate the penetrance of these mutations. 5) Estimate the frequency of ATM mutations in defined groups of unselected population-based breast cancer cases. Our findings will have numerous clinical implications, including whether women in high-risk families should be routinely or selectively screened for ATM, as well as BRCA1 and BRCA2 mutations. In addition, knowledge of ATM mutation status will allow future assessment of many clinical issues, including genetic and environmental modifiers of penetrance, appropriate surveillance, disease severity, patients' response to different treatment regimens, and possible adverse reactions to radiotherapy. The results of this research may directly affect treatment decisions, and improve preventive monitoring in high-risk families.