Risk and penetrance of mutations from breast cancer testing panels.

描述(申请人提供)：乳腺癌是美国最常见的癌症之一。大约15%到20%的病例表现出疾病的家族史，这表明有很强的遗传成分。乳腺癌的易感性与BRCA1、BRCA2、PTEN、STK11、CDH1和TP53的高外显性种系突变有关。此外，其他几个基因的遗传失活突变也与家族性乳腺癌有关。其中包括ATM、CHEK2、PALB2、BRIP1、BARD1、RAD51C、RAD51D、XRCC2、NBN、RAD50和MRE11A。虽然ATM和CHEK2的失活突变与乳腺癌风险适度增加3到7倍有关，终身风险在20%到50%之间，但这些风险估计是不准确的，而且对与其他易感基因失活突变相关的乳腺癌和其他癌症的风险知之甚少。所有这些高风险和中等风险易感基因的临床基因检测现已可用。许多有乳腺癌、卵巢癌或其他癌症个人和家族病史的女性正在利用这些检测小组进行突变检测，这些小组的需求因《安吉丽娜的故事》而激增。初步数据显示，约10%的小组测试确定了截断突变和 在已知的易感基因中，20%的变异体以错义和未明确临床相关性的内含子变化的形式产生不确定意义的变异体(VUS)。尽管可能有助于确定患者家庭中乳腺癌的病因，但在对小组测试结果的临床解释方面仍然存在显著的局限性。特别是，与年龄相关的乳腺癌和其他与基因突变相关的癌症的风险在很大程度上是未知的。此外，还没有针对突变携带者制定明确的医疗管理建议。因此，这些测试的结果可能会导致混乱和不知情的医疗决定，从而可能导致重大损害。我们建议在乳腺癌病例对照研究和高危乳腺癌家系中使用已知乳腺癌易感基因的高通量突变筛查，以确定与这些基因有害突变相关的乳腺癌和其他癌症的风险如下：目的1)使用基于队列的大型病例对照研究，确定与已知易感基因突变相关的普通人群中乳腺癌的风险；目的2)通过乳腺癌家系研究，确定与小组为基础的易感基因的失活突变相关的癌症的外显性；目的3)确定VUS在已知易感基因中的临床相关性。在研究结束时，我们希望为普通人群和乳腺癌家族建立与有害基因突变相关的风险估计，从而大大改善突变携带者的风险评估。此外，我们希望在已知的易感基因中确定许多VU的临床相关性。这项研究的结果还将提供必要的数据，为中等外显性基因有害突变携带者建立护理标准医疗管理建议，这是一个关键的未得到满足的需求。

DESCRIPTION (provided by applicant): Breast cancer is one of the most common cancers in the US. Approximately 15% to 20% of cases exhibit a family history of the disease suggesting a strong heritable component. Susceptibility to breast cancer is associated with high-penetrance germline mutations in BRCA1, BRCA2, PTEN, STK11, CDH1, and TP53. In addition, inherited inactivating mutations in several other genes have been associated with familial breast cancer. These include ATM, CHEK2, PALB2, BRIP1, BARD1, RAD51C, RAD51D, XRCC2, NBN, RAD50, and MRE11A. While inactivating mutations in ATM and CHEK2 have been associated with moderate 3 to 7-fold increased risk of breast cancer with lifetime risks of between 20% and 50%, these risk estimates are imprecise and little is known about the risk of breast and other cancers associated with inactivating mutations in the other predisposition genes. Clinical genetic testing for all of these high and moderate risk predisposition genes is now available. Many women, with personal and family history of breast, ovarian or other cancers, are pursuing testing for mutations with these panels, which has seen an upsurge in demand in response to 'Angelina's story'. Initial data suggest that ~10% of panel tests identify truncating mutations and 20% yield variants of uncertain significance (VUS) in the form of missense and intronic changes of undefined clinical relevance in the known predisposition genes. Although potentially useful for establishing the etiology of breast cancer in a patient's family, there remain significant limitatins in the clinical interpretation of the results from the panel testing. In particular, the age-relate risk of breast and other cancers associated with mutations in the genes are largely undefined. Furthermore, clear medical management recommendations for mutation carriers have not been developed. Thus, the results of these tests can lead to confusion and uninformed medical decisions that can result in significant harm. We propose to use high-throughput mutation screening of known breast cancer predisposition genes in breast cancer case-control studies and high-risk breast cancer families to establish the risks of breast and other cancers associated with deleterious mutations in these genes as follows: Aim 1) Establish the risk of breast cancer in the general population associated with mutations in known predisposition genes using large cohort-based case-control studies; Aim 2) Define the penetrance of cancers associated with inactivating mutations in panel-based predisposition genes through breast cancer family studies; Aim 3) Determine the clinical relevance of VUS in the known predisposition genes. At the conclusion of the study, we expect to establish risk estimates associated with deleterious mutations in the genes for the general population and breast cancer families, leading to much improved risk assessment for mutation carriers. In addition, we expect to establish the clinical relevance of many VUS in the known predisposition genes. The results of this study will also provide the necessary data to establish standard of care medical management recommendations for carriers of deleterious mutations in moderate penetrance genes, a critical unmet need.