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

项目总结 传统上，三阴性乳腺癌(TNBC)与已发现的基因变化相比，较少相关 亚型，排除针对肿瘤特异性依赖的治疗，如HER2或ER。然而，两者 同源重组(HR)介导的DNA修复的生殖系和体细胞丢失是TNBC的一个标志性驱动因素。 与遗传驱动因素常见的白人女性的HR修复缺陷(HRD)TNBC相比， 来自非洲血统女性的HRD基因启动子的表观遗传沉默倾向于通过 DNA甲基化。具有遗传性或表观遗传性HRD的TNBCs对PARP抑制剂治疗敏感。 不幸的是，只有一小部分HRD肿瘤有可识别的遗传或表观遗传改变，潜在地 导致错失了将从HRD靶向治疗中受益的患者的机会。 非洲血统妇女中HRD基因启动子的表观遗传沉默表明 推动者也可能导致HRD。然而，我们对反复出现的功能性启动子突变知之甚少。 在乳腺癌方面。这在一定程度上是由于技术原因导致启动子区域的基因组测序不完整 现有数据集中的挑战。我们最近开发了一种有针对性的分析方法来对启动子进行深度测序 在3,000个癌症基因启动子中。凭借我们手头的创新和独特技术，我们随时准备解决 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 导致HRD或其他治疗相关表型的癌症基因启动子的变化。我们 计划通过以下方式测试我们的假设：(I)分析来自不同患者的约120个TNBCs和匹配的正常样本 使用我们的技术在HRD和其他基因启动子中识别候选驱动程序体细胞突变 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；和(3)试行一项功能评估战略，通过在相关区域描述TP53 5‘区域的事件 细胞系模型。我们的研究具有识别HRD和HRD中新的遗传启动子改变的潜力 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，这一试点 项目(I)可以扩展到调查更大的患者队列，以发现启动子相关的驱动事件；以及 (Ii)有多学科研究小组将潜在的发现转化为与HRD临床相关的生物标记物- 未来的靶向治疗。

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.