Subclonal heterogeneity and outcome disparities in Triple-Negative Breast Cancer among African Americans

项目摘要 非裔美国人(AA)女性的乳腺癌死亡率更高，即使在 混淆的临床和社会人口学因素。这种差异在一定程度上反映了这样一个事实，即 美国女性罹患三阴性乳腺癌的可能性约为高加索女性的两倍 (TNBC)，一种特别侵袭性的乳腺癌亚群。然而，即使在患有TNBC的人中，AA种族也是 独立地与较差的治疗反应和较差的存活率相关。这些数据和其他数据 包括我们自己的工作在内，已经形成了一种新的共识，即这种超额死亡率在一定程度上是由于 再生障碍性贫血和尖锐湿疣患者TNBCs的生物学差异。例如，最近的基因组分析已经 在AA妇女的TNBCs中显示出明显的体细胞突变特征。我们最近对基因的分析 根据RACE对TNBC亚型的表达表明，AA妇女疾病进展的增加是 对于固有的基本TNBC亚集具有选择性。在另一项单独的研究中，我们和合作者证明了 AA和CA患者TNBCs同源重组(HR)缺陷的机制最后，我们 还发现推断的亚克隆异质性，一种反映恶性细胞亚群的指标 在已知与TNBC临床预后不良相关的肿瘤内，在 AA组与CA组的TNBCs比较。这一发现可能解释了为什么大宗肿瘤分析在很大程度上未能 为AA和CA女性之间的TNBC的生物学差异提供机械性或可操作的见解。 总的来说，这些发现支持这样的假设，即不同的肿瘤特征包括增加 亚克隆性异质性导致患有TNBC的再障女性的临床预后较差。这些结果 有必要对再障妇女的TNBC生物学进行重点和详细的研究。因此，我们发起了一项 协调、创新和高度协同的机构间协作，汇聚领先的 具有互补专业知识的调查人员，采用最先进的方法来解决这一未满足的问题 需要。我们建议对TNBCs进行基因组、表观遗传学和基因表达谱分析，包括单细胞分析 在再生障碍性贫血和其他女性中进行研究，以揭示导致再生障碍性贫血患者预后较差的驱动因素 发现新的、在治疗上可行的干预方法。我们将识别驾驶员路径和细胞 再生障碍性贫血和尖锐湿疣妇女中与新辅助化疗初次反应相关的亚群 与TNBC合作。然后，我们将检查克隆选择，并通过前/后发现抗性亚群 再生障碍性贫血患者的新辅助化疗分析。下一步，我们将确定种族的患病率 基因组/表观遗传学改变和细胞亚群及其预测长期结果的能力 回顾性的TNBC队列分析。最后，我们将建立原代TNBC的体外模型和PDX模型。 具体的机制和治疗性假设检验。总而言之，这些研究将提供以下手段 快速临床翻译，并将使患有TNBC的AA妇女能够进行个性化治疗。

Project Summary African American (AA) women experience higher rates of breast cancer mortality, even when accounting for confounding clinical and sociodemographic factors. This disparity reflects in part the fact that AA women in the US are approximately twice as likely as Caucasian (CA) women to develop Triple-Negative Breast Cancer (TNBC), a particularly aggressive breast cancer subset. However, even among those with TNBC, AA race is independently associated with inferior treatment responses and poorer survival rates. These and other data including our own work have led to an emerging consensus that that this excess mortality is due in part to biological differences between TNBCs in AA versus CA women. For example, recent genomic analyses have demonstrated distinct somatic mutation profiles in TNBCs among AA women. Our recent analysis of gene expression subtypes of TNBC by race showed that the increase in disease progression among AA women was selective for the intrinsic basal TNBC subset. In a separate study, we and collaborators demonstrated distinct mechanisms of homologous recombination (HR) deficiency in TNBCs from AA versus CA women. Finally, we also discovered that inferred subclonal heterogeneity, a measure reflecting malignant cell sub-populations within the tumor that is known to be associated with poor clinical outcomes in TNBC, in significantly higher in TNBCs of AA compared to CA women. This finding may explain why bulk tumor analysis has largely failed to provide mechanistic or actionable insights into the biological differences in TNBC between AA and CA women. Collectively, these findings support the hypothesis that distinct tumor characteristics including increased subclonal heterogeneity contribute to poorer clinical outcomes for AA women with TNBC. These results warrant a focused and detailed investigation of TNBC biology in AA women. Accordingly, we have initiated a coordinated, innovative and highly synergistic inter-institution collaboration, bringing together leading investigators with complementary expertise, employing state-of-the-art methodologies to address this unmet need. We propose genomic, epigenetic and gene expression profiling including single-cell analysis in TNBCs among AA and other women in order to reveal drivers that explain poorer outcomes in the AA population and discover new, therapeutically actionable means of intervening. We will Identify driver pathways and cell subpopulations that correlate with primary response to neoadjuvant chemotherapy among AA vs. CA women with TNBC. We will then examine clonal selection and discover resistant sub-populations through pre/post neoadjuvant chemotherapy analysis of TNBC in AA women. Next, we will determine the prevalence by race of genomic/epigenetic alterations and cell subpopulations and their ability to predict long-term outcomes through retrospective TNBC cohort analysis. Finally, we will establish ex vivo and PDX models of primary TNBC for specific mechanistic and therapeutic hypothesis testing. Together, these studies will provide the means for rapid clinical translation and will enable personalized therapy for AA women with TNBC.