Resolving the cancer relevance of predisposition gene mutations

乳腺癌具有很强的遗传性，约15%的患者有家族史 疾病。我的小组最近确定了12个基因（ATM，BARD 1，BRCA 1，BRCA 2， CDH 1、CHEK 2、NF 1、PALB 2、PTEN、RAD 51 C、RAD 51 D和TP 53）易患乳腺癌（1，2）， 所有12个基因的变异都会增加少数群体患乳腺癌的风险（3），某些基因的变异会增加少数群体患乳腺癌的风险。 基因仅倾向于雌激素受体（ER）阳性（ATM和CHEK 2）或ER阴性和三阴性 乳腺癌（TNBC）（BARD 1、RAD 51 C和RAD 51 D）（4-6）。尽管取得了这些重大进展， 信息仍然缺乏。此外，高达50%的乳腺癌家族风险仍然无法解释。 根据该奖项，我们计划解决临床相关问题，包括改进基因检测的应用 结果用于患者的风险管理和改善乳腺癌治疗的选择。此外，我们的目标是 确定新的乳腺癌易感基因，解释缺失的遗传性。拟议的研究 统一在一个主题下，即推进对易感性遗传学的理解。这些研究如下： A.易感基因变异的个体特异性和人群特异性癌症风险评估。结果 遗传性多基因组检测的临床效用有限，因为只有通过年龄来估计癌症的终生风险， 80可用在这里我们将估计5年和10年患乳腺癌的风险，以便患者做出决定 关于医疗管理。此外，我们有证据表明，特定的基因有更高的同源性， 非裔美国人我们将使用一个大的非洲人来确定易感基因变异的频率。 美国队列研究，以修改该人群的风险管理指南。 B。易感基因变异体的功能表征。重要性不确定变量（VUS） 对于接受临床基因检测的个人来说，通过基因检测鉴定的人仍然是一个主要问题。我们的目标是 联合收割机将ATM、BRCA 2和PALB 2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已知基因仅为BRCA 1， BRCA 2突变携带者。在这里，我们的目标是确定所有患者的致病性变异，在常见的突变， 来自一系列新辅助、辅助和转移性乳腺癌的BRCA 1、BRCA 2、PALB 2、ATM和CHEK 2基因 癌症临床试验，并评估对治疗的反应和结果。 D.新的乳腺癌易感等位基因的鉴定。乳腺癌的常见和罕见风险等位基因 癌症仅占人口中家族风险的50%。为了找出缺失的遗传性 我们将与Regeneron Inc.通过我们的SIMPLEXO联盟来鉴定常见和罕见的等位基因 与45，000名乳腺癌患者的乳腺癌风险相关。

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.