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

项目摘要 传统上，三阴性乳腺癌（TNBC）与其他乳腺癌相比， 亚型，排除靶向肿瘤特异性依赖性（如HER 2或ER）的治疗。但无论 同源重组（HR）介导的DNA修复的种系和体细胞损失是TNBC的标志性驱动因素。 与遗传驱动因素常见的白色女性的HR修复缺陷（HRD）TNBC相比， 来自非洲血统妇女的HRD基因启动子的表观遗传沉默倾向于富集， DNA甲基化具有遗传或表观遗传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， 导致患者错过了从HRD靶向治疗中获益的机会。 非洲血统女性HRD基因启动子的表观遗传沉默表明， 启动子也可能导致HRD。然而，我们对经常性的功能性启动子突变知之甚少， 在乳腺癌中。这部分是由启动子区域的不完全基因组测序引起的，这是由于技术上的限制。 现有数据集的挑战。我们最近开发了一种靶向测定法， 超过3,000个癌症基因启动子。凭借我们的创新和独特的技术，我们已准备好解决 来自非洲血统女性的TNBC具有可操作的遗传驱动因素的中心假设 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 我计划通过（i）分析来自不同患者的~120个TNBC和匹配的正常样本来测试我们的假设 用我们的技术鉴定HRD和其他基因启动子中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、治疗反应和临床表现相关联。 结果;和（iii）通过描述TP 53 5'区域的相关事件， 细胞系模型。我们的研究有可能确定HRD中新的遗传启动子改变， 在具有侵袭性TNBC的来自不同血统的患者中，可能存在其他癌症基因。如果成功，这名飞行员 项目（i）可以被缩放以调查更大的患者群体，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- 未来的治疗目标。

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.