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

非裔美国人三阴性乳腺癌的亚克隆异质性和结果差异

基本信息

批准号：
10347682
负责人：
LEIF W ELLISEN
金额：
$ 75.12万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10347682
关键词：
Accounting Address African American African American population Area Biological Biological Markers Biology Boston Breast Cancer Patient Cancer Biology Caucasians Cells Characteristics Chemoresistance Clinical Cohort Analysis Collaborations Complement Consensus Data Disease Disease Progression Epigenetic Process Excess Mortality FBXW7 gene Gene Expression Profiling Genes Genomics Germ-Line Mutation Hospitals Inferior Institution Investigation Measures Medical center Methodology Methylation Minor Molecular Analysis Mutation Neoadjuvant Therapy New England Outcome Pathway interactions Patients Pharmacology Study Population Prevalence Publishing Race Relapse Research Research Personnel Residual Tumors Resistance Socioeconomic Status Somatic Mutation Specimen Survival Rate Testing Therapeutic Tissue Microarray Treatment outcome Tumor Suppressor Proteins Underserved Population Woman Work aggressive breast cancer cancer cell cancer health disparity chemotherapy clinical care clinical translation cohort driver mutation drug sensitivity epigenetic silencing epigenomics experience experimental study homologous recombination innovation insight malignant breast neoplasm molecular subtypes mortality neoplastic cell novel novel therapeutics outcome prediction patient derived xenograft model personalized approach personalized medicine predictive marker prognostic ras GTPase-Activating Proteins response safety net single cell analysis single-cell RNA sequencing sociodemographic factors subclonal heterogeneity treatment response triple-negative invasive breast carcinoma tumor tumor heterogeneity

项目摘要

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.

项目概要非裔美国 (AA) 女性的乳腺癌死亡率较高，即使考虑到混淆临床和社会人口因素。这种差异部分反映了 AA 女性在美国女性患三阴性乳腺癌的可能性大约是白人 (CA) 女性的两倍（TNBC），一种特别具有侵袭性的乳腺癌亚型。然而，即使在 TNBC 的人中，AA 种族也是如此与较差的治疗反应和较低的生存率独立相关。这些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，即死亡率过高的部分原因是 AA 与 CA 女性 TNBC 之间的生物学差异。例如，最近的基因组分析表明在 AA 女性的 TNBC 中显示出独特的体细胞突变谱。我们最近对基因的分析按种族划分的 TNBC 表达亚型表明，AA 女性疾病进展的增加是对内在基础 TNBC 子集具有选择性。在一项单独的研究中，我们和合作者展示了不同的 AA 与 CA 女性 TNBC 中同源重组 (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已知与 TNBC 不良临床结果相关的肿瘤内， AA 女性与 CA 女性的 TNBC 比较。这一发现可能解释了为什么大块肿瘤分析在很大程度上未能提供关于 AA 和 CA 女性 TNBC 生物学差异的机制或可操作的见解。总的来说，这些发现支持这样的假设：不同的肿瘤特征包括增加亚克隆异质性导致患有 TNBC 的 AA 女性临床结果较差。这些结果需要对 AA 女性的 TNBC 生物学进行重点和详细的调查。据此，我们发起了一项协调、创新和高度协同的机构间合作，汇聚领先优势具有互补专业知识的研究人员，采用最先进的方法来解决这一未满足的问题需要。我们提出基因组、表观遗传学和基因表达谱分析，包括 TNBC 中的单细胞分析在 AA 和其他女性中进行调查，以揭示解释 AA 人群中较差结果的驱动因素，以及发现新的、治疗上可行的干预手段。我们将识别驱动路径和细胞与 AA 与 CA 女性新辅助化疗主要反应相关的亚群与 TNBC 合作。然后，我们将检查克隆选择并通过前/后发现耐药亚群 AA 女性 TNBC 的新辅助化疗分析。接下来，我们将确定按种族划分的患病率基因组/表观遗传改变和细胞亚群及其通过预测长期结果的能力回顾性 TNBC 队列分析。最后，我们将建立原发性 TNBC 的离体和 PDX 模型，用于具体机制和治疗假设检验。总之，这些研究将为快速临床转化，将为患有 TNBC 的 AA 女性提供个性化治疗。