High Frequency of CHD1 Loss in BRCA2- Deficient African American Prostate Tumors Drives Tumor Formation by Suppressing Replication Stress

BRCA2 缺陷型非裔美国前列腺肿瘤中 CHD1 的高频率缺失通过抑制复制应激来驱动肿瘤形成

• 批准号: 10328013
• 负责人: Zoltan Szallasi
• 金额: $ 8.03万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328013
• 关键词: African; African American; American; Applications Grants; BRCA2 gene; Biological; Boston; CHD1 gene; CRISPR/Cas technology; Cancer Center; Cells; Chemoresistance; Cisplatin; Clinical; DNA Sequence Alteration; Disease Outcome; Down-Regulation; European; Face; Frequencies; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Transcription; Germ-Line Mutation; Incidence; Malignant neoplasm of prostate; Mammary Neoplasms; Massachusetts; Mutate; Mutation; Outcome; Platinum; Poly(ADP-ribose) Polymerases; Prostate; Prostate Adenocarcinoma; Prostatic Neoplasms; Proteins; Research; Resistance; Testing; Therapeutic; Tissues; Universities; Work; base; cancer health disparity; cancer type; chemotherapeutic agent; homologous recombination; inhibitor/antagonist; men; mortality; mutation carrier; racial disparity; replication stress; response; therapeutic target; therapy resistant; tool; tumor; whole genome

PROJECT SUMMARY/ ABSTRACT. Prostatic adenocarcinoma is a cancer type with one of the most significant racial disparity both in terms of incidence and mortality. Men of African ancestry have a significantly worse outcome with a 2.4-fold increased mortality rate compared with men of European ancestry. While the reasons underlying these disparities are multifactorial, there is accumulating evidence that a significant biological and/or genetic component may be at least partially responsible for this difference. Work proposed in this grant proposal tests one such genetic component which has been identified through complementary preliminary studies in both Dr. Szallasi’s and Dr. Pathania’s groups. Dr. Szallasi’s group has discovered that subclonal CHD1 (Chromodomain-helicase-DNA-binding protein 1) loss is significantly more frequent in prostate cancer cases of African Americans (AA) than in European Americans (EA) (40% vs. 15% respectively). A whole genome CRISPR-Cas9 based screen carried out by Dr. Pathania’s group has identified CHD1 as one of the top gene hits which, when depleted, allowed BRCA2 deficient cells to grow in the presence of cisplatin (commonly used chemotherapeutic agent). This is an important observation, because BRCA2 deficient prostate cancer cases, due to the associated homologous recombination deficiency, are increasingly considered for platinum or PARP inhibitor-based therapy. Our results suggest that CHD1 loss may be an escape mechanism for BRCA2 (homologous recombination) deficient prostate cancer and this escape mechanism seems to be activated more frequently in African American cases leading to their more frequent resistance to therapy. We propose to test this hypothesis in this grant application. While germline BRCA2 mutations are not frequent in prostate cancer cases, we speculate that BRCA2 deficiency is more common than documented and could account for at least 20% of the cases. We suggest this because loss of BRCA2 is not only induced by heterozygous deletion of BRCA2 (in germline mutation carriers) but BRCA2 deficiency can also be acquired by mutation in SPOP gene which has been shown previously to transcriptionally regulate BRCA2. SPOP gene is one of the most frequently mutated gene in prostate cancer. We propose to understand the dynamics of CHD1 loss, SPOP loss, and BRCA2 expression and its effect on therapy response in AA men. Completion of this study will provide us with tools to identify early changes that occur in prostate tissue of AA prostate tissue and identify those AA prostate cancer cases that can most benefit from PARPi and cisplatin-based therapeutic strategies. Finally, the fact that AA men with prostate cancer face significantly worse clinical outcome than their European American counterparts, identifying a therapeutically targetable biological mechanism for this difference, and to understand the drivers of chemotherapy resistance in African American men could significantly reduce the racial disparity in the overall outcome of the disease.

项目摘要/摘要。前列腺癌是一种癌症类型，是世界上 在发病率和死亡率方面都存在明显的种族差异。非洲血统的男性有显著的 结果更糟，死亡率是欧洲血统男性的2.4倍。而当 造成这些差异的原因是多方面的，有越来越多的证据表明， 生物和/或遗传成分可能至少是造成这种差异的部分原因。建议开展的工作 这项拨款提案测试了一种这样的遗传成分，它已经通过互补 在萨拉西博士和帕塔尼亚博士的小组中进行的初步研究。Szallasi博士的研究小组发现 亚克隆性CHD1(Chromodomain-Helicase-DNA-BindingProtein 1)丢失在 非洲裔美国人(AA)的前列腺癌病例(40%)高于欧洲裔美国人(EA)的前列腺癌病例(15%) )。由巴塔尼亚博士的团队进行的基于CRISPR-Cas9的全基因组筛查发现 CHD1作为最重要的基因之一，当被耗尽时，允许BRCA2缺陷细胞在 顺铂(常用化疗药物)的存在。这是一个重要的观察结果，因为 BRCA2缺乏的前列腺癌病例，由于相关的同源重组缺陷，是 越来越多的人考虑使用铂或PARP抑制剂进行治疗。我们的结果表明CHD1的丢失可能 是BRCA2(同源重组)缺陷前列腺癌的逃逸机制 在非裔美国人的案例中，机制似乎更频繁地被激活，导致他们更频繁地 对治疗的抗拒。我们建议在这项拨款申请中检验这一假设。 虽然生殖系BRCA2突变在前列腺癌病例中并不常见，但我们推测BRCA2 缺乏症比文献记载的更常见，可能至少占病例的20%。我们建议这样做 因为BRCA2的丢失不仅是由于BRCA2杂合缺失(在胚系突变携带者中) 但BRCA2缺乏症也可以通过SPOP基因的突变而获得，这在以前已经被证明是 转录调控BRCA2。SPOP基因是前列腺癌中最常见的突变基因之一。 我们建议了解CHD1丢失、SPOP丢失和BRCA2表达的动态及其对 再障男性的治疗反应。这项研究的完成将为我们提供工具来识别早期的变化， 在AA前列腺癌组织中发生，并确定哪些AA前列腺癌病例最容易 受益于PARPI和基于顺铂的治疗策略。 最后，患有前列腺癌的AA患者面临的临床结果明显比他们的 欧美同行，确定了一种治疗靶向的生物机制 差异，了解非洲裔美国人男性化疗耐药的驱动因素可能 显著减少该病总体结局中的种族差异。