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

• 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
• 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

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。然而，两者 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， 促销员也可能导致HRD。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。 现有数据集的挑战。我们最近开发了一种靶向测定法来对启动子进行深度测序 > 3,000 个癌症基因启动子。凭借我们现有的创新和独特技术，我们已准备好解决 核心假设是非洲血统女性的 TNBC 含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。我们 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 细胞系模型。我们的研究有可能发现 HRD 中新的遗传启动子改变 来自不同血统的侵袭性 TNBC 患者中可能存在其他癌症基因。如果成功的话，这个试点 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；和 (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。