The role of the ATM gene in familial breast cancer

描述（由申请人提供）：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了4-7倍，但对未选择的乳腺癌病例中ATM基因的突变分析未能发现令人信服的频率比对照组高。然而，我们已经表明，ATM基因的两种特定致病性突变确实发生在4%的多病例乳腺癌家族中，并赋予乳腺癌的高风险，相当于70岁的风险为60%。本提案的广泛目标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，从而扩展我们的发现。我们的具体目标是：1)对900个乳腺癌家族中最年轻的受影响女性进行ATM突变筛查。2)通过分析这些变异在携带这些变异的女性的肿瘤和细胞系中的行为，在这些变异中确定假定的ATM突变。3)对另外2000个乳腺癌家族进行筛查，以确定Aim 2中定义的可能的ATM突变。4)对携带推测的ATM突变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)估计在未选择的基于人群的乳腺癌病例的确定组中ATM突变的频率。我们的研究结果将有许多临床意义，包括高风险家庭的女性是否应该常规或选择性地筛查ATM，以及BRCA1和BRCA2突变。此外，对ATM突变状态的了解将允许未来对许多临床问题进行评估，包括外显率的遗传和环境修饰因素、适当的监测、疾病严重程度、患者对不同治疗方案的反应以及对放疗可能的不良反应。本研究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.