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.

项目概要与其他乳腺癌相比，三阴性乳腺癌 (TNBC) 传统上与已发现的基因变化较少相关。亚型，排除针对肿瘤特异性依赖性的治疗，例如 HER2 或 ER。同源重组 (HR) 介导的 DNA 修复的种系和体细胞丢失是 TNBC 的标志性驱动因素。与遗传驱动因素常见的白人女性 HR 修复缺陷 (HRD) TNBC 相比，这些来自非洲血统的女性的 HRD 基因启动子的表观遗传沉默往往通过 DNA 甲基化具有遗传性或表观遗传性 HRD 的 TNBC 对 PARP 抑制剂治疗敏感。不幸的是，只有一小部分 HRD 肿瘤具有可识别的遗传或表观遗传改变，可能导致患者错失从 HRD 针对性治疗中受益的机会。非洲血统女性 HRD 基因启动子的表观遗传沉默表明，然而，我们对复发性功能性启动子突变知之甚少。在乳腺癌中，这部分是由于技术原因导致启动子区域基因组测序不完整造成的。我们最近开发了一种有针对性的检测方法来对启动子进行深度测序。凭借我们现有的创新和独特技术，我们已准备好解决超过 3,000 个癌症基因启动子的问题。核心假设是非洲血统女性的 TNBC 具有可操作的基因驱动因素诱导 HRD 或其他治疗相关表型的癌症基因启动子的改变。计划通过 (i) 对来自不同患者的约 120 个 TNBC 和匹配的正常样本进行分析来检验我们的假设使用我们的技术识别 HRD 启动子和其他启动子的候选驱动体细胞突变癌症基因；(ii) 将这些突变与匹配的基因表达、治疗反应和临床联系起来结果；(iii) 通过描述 TP53 5' 区域相关事件的特征来试点功能评估策略我们的研究有可能识别 HRD 和细胞系中新的遗传启动子改变。如果成功，该试验将在来自不同血统的侵袭性 TNBC 患者中发现潜在的其他癌症基因。项目 (i) 可以扩大规模以研究更大的患者群体，以发现启动子相关的驱动事件；以及 (ii) 拥有多学科研究团队，将潜在的发现转化为 HRD 的临床相关生物标志物未来有针对性的治疗。