Landscape and characterization of promoter mutations driving triple-negative breast cancer

驱动三阴性乳腺癌的启动子突变的景观和特征

基本信息

批准号：
10751219
负责人：
LEIF W ELLISEN
金额：
$ 24.97万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-13 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751219
关键词：
Address Affect African ancestry Asian Automobile Driving BRCA1 gene Binding Binding Proteins Binding Sites Biological Assay Biological Markers Blood Boston Breast Cancer Model Breast Cancer Patient Cell Line Cells Cellular Stress Clinical Clustered Regularly Interspaced Short Palindromic Repeats Code Collaborations DNA DNA Methylation DNA Repair DNA Sequence Data Data Set Dependence Detection Dropout ERBB2 gene Eligibility Determination Enhancers Ensure Epigenetic Process Estrogen Antagonists Estrogen Receptors Evaluation Event Family Frequencies Future Gene Expression Genes Genetic Genome Genomics Germ-Line Mutation Hand Hospitals In Vitro MCF7 cell Malignant Neoplasms Mediating Medical center Methylation Mexican Modeling Molecular Mutation New England Nucleic Acid Regulatory Sequences Oncogenes Outcome Patients Phenotype Pilot Projects Poly(ADP-ribose) Polymerase Inhibitor Population Heterogeneity Predisposition Promoter Regions Proteins Publishing RAD51C gene Recurrence Research Resistance Risk Sampling Somatic Mutation Specimen TP53 gene Technology Testing The Cancer Genome Atlas Therapeutic Tissues Translating Tumor Suppressor Proteins Untranslated RNA Validation Variant Woman activating transcription factor brca gene cancer genome cancer type candidate identification clinically relevant cohort driver mutation drug sensitivity epigenetic silencing epigenomics exome exome sequencing homologous recombination in silico inhibitor therapy innovation malignant breast neoplasm multidisciplinary novel patient population promoter recombinational repair recruit safety net targeted treatment therapy outcome transcription factor transcriptomics treatment response triple-negative invasive breast carcinoma tumor tumor progression whole genome

项目摘要

PROJECT SUMMARY Triple-negative breast cancer (TNBC) is traditionally associated with fewer identified genetic changes than other subtypes, precluding therapies that target tumor-specific dependencies such as HER2 or ER. However, both germline and somatic loss of homologous recombination (HR)-mediated DNA repair is a hallmark driver of TNBC. Compared to HR repair deficiency (HRD) TNBC from white women in which genetic drivers are common, those from women of African ancestry tend to be enriched for epigenetic silencing of HRD gene promoters through DNA methylation. TNBCs with either genetic or epigenetic HRD are susceptible to PARP inhibitor therapy. Unfortunately, only a fraction of HRD tumors have an identifiable genetic or epigenetic alteration, potentially leading to missed opportunities for patients who would benefit from HRD-targeted treatment. Epigenetic silencing of HRD gene promoters in women of African ancestry suggests that somatic alterations of promoters could also cause HRD. However, we know very little about recurrent, functional promoter mutations in breast cancer. This is partially caused by incomplete genomic sequencing at promoter regions due to technical challenges in existing datasets. We have recently developed a targeted assay to deeply sequence the promoters of >3,000 cancer gene promoters. With our innovative and unique technology at hand, we are ready to address the central hypothesis that TNBC from women of African ancestry harbor actionable genetic driver alterations in cancer gene promoters that induce HRD or other therapeutically relevant phenotypes. We plan to test our hypothesis by (i) profiling ~120 TNBCs and matched normal samples from a diverse patient population with our technology to identify candidate driver somatic mutation in promoters of HRD and other cancer genes; (ii) associate these mutations with matched gene expression, treatment response and clinical outcome; and (iii) pilot a functional evaluation strategy by characterizing events in the TP53 5’ region in relevant cell line models. Our research carries the potential to identify novel genetic promoter alterations in HRD and potentially other cancer genes in patients from diverse ancestries with aggressive TNBC. If successful, this pilot project (i) can be scaled to investigate larger patient cohorts to discover promoter-associated driver events; and (ii) has the multidisciplinary study team to translate potential findings into clinically relevant biomarkers for HRD- targeted treatment in the future.

项目摘要传统上，三阴性乳腺癌（TNBC）与其他遗传变化有关亚型，排除针对肿瘤特异性依赖性（例如HER2或ER）的疗法。但是，这两个生殖线和同源重组（HR）介导的DNA修复的躯体丧失是TNBC的标志驱动力。与来自遗传驱动因素的白人妇女的人力资源维修不足（HRD）TNBC相比来自非洲血统的妇女往往会因通过 DNA甲基化。具有遗传或表观遗传HRD的TNBC容易受到PARP抑制剂治疗的影响。不幸的是，只有一部分HRD肿瘤具有可识别的遗传或表观遗传改变，可能有可能为将受益于HRD靶向治疗的患者带来错过的机会。非洲血统妇女中HRD基因启动子的表观遗传沉默表明，发起人也可能导致HRD。但是，我们对复发性功能启动子突变知之甚少在乳腺癌中。由于技术，这部分是由于启动子区域的不完整基因组测序引起的现有数据集中的挑战。我们最近开发了一种有针对性的测定，以深入启动子 > 3,000个癌症基因启动子。凭借我们的创新和独特的技术，我们准备解决非洲血统港妇女的TNBC的中心假设可行的遗传驱动器诱导HRD或其他治疗相关表型的癌症基因启动子的改变。我们计划通过（i）分析〜120 TNBC测试我们的假设，并匹配来自潜水员患者的正常样本人口具有我们的技术，以识别HRD促进者的候选驾驶员躯体突变癌基因；（ii）将这些突变与匹配的基因表达，治疗反应和临床相关联结果; （iii）通过表征相关的TP53 5'区域中的事件来实现功能评估策略单元线模型。我们的研究具有鉴定HRD中新型遗传启动子改变的潜力来自具有侵略性TNBC的潜水祖先患者的其他癌症基因。如果成功，这个飞行员可以将项目（i）缩放以调查更大的患者队列，以发现与启动子相关的驾驶员事件；和（ii）拥有多学科研究团队，可以将潜在的发现转化为HRD-的临床相关生物标志物将来有针对性的治疗。