Resolving the cancer relevance of predisposition gene mutations

乳腺癌有很强的遗传性，大约15%的患者有家族病史 这种疾病的危害。我的团队最近发现，12个基因(ATM、BARD1、BRCA1、BRCA2、 CDH1、CHEK2、NF1、PALB2、PTEN、RAD51C、RAD51D和TP53)易患乳腺癌(1、2)， 在少数民族人群中，所有12个基因的变异都会增加患乳腺癌的风险(3)，而且某些基因的变异 基因只对雌激素受体(ER)阳性(ATM和CHEK2)或ER阴性和三阴性易感 乳腺癌(TNBC)(BARD1、RAD51C和RAD51D)(4-6)。尽管取得了这些重大进展，但临床应用 目前仍缺乏相关信息。此外，高达50%的乳腺癌家族风险仍未得到解释。 根据这个奖项，我们计划解决与临床相关的问题，包括改进基因检测的应用 为患者的风险管理和改进乳腺癌治疗的选择提供了结果。此外，我们的目标是 找出新的乳腺癌易感基因，解释缺失的遗传性。建议进行的研究 都统一在一个主题下，即推进对易感遗传学的理解。研究内容如下： A.针对易感基因变异的特定年龄和特定人群的癌症风险评估。结果来自 遗传性多基因小组检测的临床应用有限，因为只有按年龄对癌症的终生风险进行评估 有80个可用。在这里，我们将评估乳腺癌的5年和10年风险，以便患者做出决定。 关于医疗管理。此外，我们有证据表明，特定的基因在 非裔美国人。我们将使用一个大型非洲人来确定易感基因变异的外显率。 美国队列研究，以修改这一人群的风险管理指南。 B.易感基因变异的功能特征。不确定意义的变种(VU) 对于接受临床基因检测的个人来说，通过基因检测进行鉴定仍然是一个主要问题。我们的目标是 将ATM、BRCA2和PALB2基因中VUS的高通量功能分析与来自 综合模型中的家庭，以确定许多VUS改变的临床相关性。 C.乳腺癌易感基因的治疗反应。乳腺肿瘤的反应性 与标准或靶向治疗的易感基因变异相关的只有BRCA1和 BRCA2突变携带者。在这里，我们的目标是确定所有患者的致病变异在常见的突变 一系列新佐剂、佐剂和转移性乳腺癌的BRCA1、BRCA2、PALB2、ATM和CHEK2基因 癌症临床试验，并评估治疗反应和结果。 D.新的乳腺癌易感基因的鉴定。乳房常见和罕见的危险等位基因 癌症仅占人口家族风险的50%。为了找出遗失的遗传性 我们将通过我们的SIMPLEXO联盟与Regeneron Inc.合作，识别常见和罕见的等位基因 在45,000名乳腺癌患者中与乳腺癌风险相关。

Breast cancer has a strong heritable component with approximately 15% of patients exhibiting a family history of the disease. My group recently established that inherited variants in 12 genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53) predispose to breast cancer (1, 2), that variants in all 12 genes increase risks of breast cancer in minority populations (3), and that variants in certain genes predispose only to estrogen receptor (ER) positive (ATM and CHEK2) or ER negative and triple negative breast cancer (TNBC) (BARD1, RAD51C and RAD51D) (4-6). Despite these major advances, clinical application of the information is still lacking. In addition, up to 50% of the familial risk of breast cancer remains unexplained. Under this award we plan to address clinically relevant issues, including improved application of genetic testing results for risk management of patients and improved selection of breast cancer therapy. In addition, we aim to identify new breast cancer predisposition genes that account for the missing heritability. The proposed studies are unified under a theme of advancing understanding of predisposition genetics. The studies are as follows: A. Age-specific and population-specific cancer risk assessment for predisposition gene variants. Results from hereditary multigene panel testing has limited clinical utility because only lifetime risk estimates of cancer by age 80 are available. Here we will estimate 5 and 10-year risks of breast cancer, so that patients can make decisions about medical management. In addition, we have evidence that specific genes have much higher penetrance in African Americans. We will determine the penetrance of predisposition gene variants using a large African American cohort study in order to modify risk management guidelines for this population. B. Functional characterization of predisposition gene variants. Variants of uncertain significance (VUS) identified by genetic testing remain a major problem for individuals receiving clinical genetic testing. We aim to combine high-throughput functional analysis of VUS in ATM, BRCA2 and PALB2 genes with genetic data from families in integrated models to determine the clinical relevance of many VUS alterations. C. Therapeutic response for breast cancer predisposition genes. The responsiveness of breast tumors associated with predisposition gene variants to standard or targeted therapy is only known for BRCA1 and BRCA2 mutation carriers. Here we aim to identify all patients with pathogenic variants in the commonly mutated BRCA1, BRCA2, PALB2, ATM and CHEK2 genes from a series of neo-adjuvant, adjuvant and metastatic breast cancer clinical trials and to assess response to therapy and outcome. D. Identification of novel breast cancer predisposition alleles. The common and rare risk alleles for breast cancer account for only 50% of the familial risk in the population. In an effort to identify the missing heritability we will collaborate with Regeneron Inc. through our SIMPLEXO consortium to identify common and rare alleles associated with breast cancer risk in 45,000 breast cancer patients.