Risk and penetrance of mutations from breast cancer testing panels.

描述（由申请人提供）：乳腺癌是美国最常见的癌症之一。大约15%至20%的病例显示出该疾病的家族史，这表明有很强的遗传成分。乳腺癌易感性与BRCA 1、BRCA 2、PTEN、STK 11、CDH 1和TP 53的高突变率生殖系突变相关。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。这些包括ATM、CHEK 2、PALB 2、BRIP 1、BARD 1、RAD 51 C、RAD 51 D、XRCC 2、NBN、RAD 50和MRE 11 A。虽然ATM和CHEK 2中的失活突变与乳腺癌风险中度增加3至7倍相关，终生风险在20%至50%之间，但这些风险估计是不精确的，并且对与其他易感基因中的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在都是可用的。许多有乳腺癌、卵巢癌或其他癌症个人和家族史的女性正在寻求用这些面板进行突变检测，这些面板的需求因“安吉丽娜的故事”而激增。初步数据表明，约10%的面板测试确定截短突变， 20%产生不确定意义（VUS）的变体，其形式为已知易感基因中不确定临床相关性的错义和内含子变化。尽管对确定患者家族中乳腺癌的病因可能有用，但在对小组测试结果的临床解释中仍然存在显著的局限性。特别是，与基因突变相关的乳腺癌和其他癌症的年龄相关风险在很大程度上是不确定的。此外，还没有为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导致混乱和不知情的医疗决定，可能导致重大伤害。我们建议在乳腺癌病例对照研究和高危乳腺癌家族中使用已知乳腺癌易感基因的高通量突变筛查来确定与这些基因中的有害突变相关的乳腺癌和其他癌症的风险，如下：目的1）使用基于大队列的病例对照研究来确定与已知易感基因中的突变相关的一般人群中的乳腺癌风险;目的2）通过乳腺癌家系研究确定与基于小组的易感基因失活突变相关的癌症的发病率;目的3）确定已知易感基因中VUS的临床相关性。在研究结束时，我们希望建立与一般人群和乳腺癌家族基因中有害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，我们期望在已知的易感基因中建立许多VUS的临床相关性。这项研究的结果还将提供必要的数据，以建立标准的护理医疗管理建议的载体中的有害突变的中度突变基因，一个关键的未满足的需求。

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.