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: 10490389
• 负责人: Zoltan Szallasi
• 金额: $ 3.41万
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490389
• 关键词: African American; African American population; African ancestry; 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; men; mortality; mutation carrier; racial disparity; replication stress; response; therapeutic target; therapy resistant; tool; treatment response; 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。 在发病率和死亡率方面，种族重要性很大。 与欧洲血统相比，死亡率增加了2.4倍 差异的原因是多因素，这是积累的证据表明这是重要的 生物学和/或遗传成分至少对差异的作用至少是部分反应 该赠款提案测试了一种通过互补的遗传成分 在Szallasi博士和Pathania博士的小组中进行预预学研究。 亚克隆CHD1（染色体蛋白酶 - 螺旋酶-DNA结合蛋白1）损耗在 非洲裔美国人（AA）的前列腺癌疾病（EA）（EA）（40％比15％） 分别是基于基因组CRISPR-CAS9的屏幕。 CHD1作为最高基因的命中之一，当深度深度允许BRCA2缺乏细胞在您的IN中生长 顺铂的存在（通常使用的化学治疗剂）。 由于相关的同源重组限定，BRCA2缺乏前列腺癌病例是 越来越多地考虑了铂或PARP抑制剂的治疗。 成为BRCA2（同源重组）缺乏前列腺脱落的逃生机制，此逃生 在非洲裔美国美国的卡斯中似乎更频繁地激活机制，从而使其更频繁 对治疗的抵抗力。 虽然在前列腺癌病例中种系BRCA2突变并不常见，但我们指定BRCA2 缺乏症比记录的更为普遍，我们至少占案件的20％ 因为BRCA2的杂合缺失不会诱导BRCA2的损失（在种系突变载体中） 但是BRCA2缺乏症也可以通过突变中的SPOP基因中获得 转录正规BRCA2是前列腺癌中最柔和的基因之一。 我们建议了解CHD1损失，铲子损失和BRCA2表达的动态，并且是ETS对 AA男士的治疗反应。 发生在AA前列腺组织的前列腺组织中，并确定那些大多数可以 受益于PARPI和基于顺铂的治疗策略。 最后，患有前列腺癌的男性面临的临床结果明显比他们的临床结果明显差。 欧美对应物，确定了一种治疗性的目标生物学机制 差异，并了解非裔美国人男性化疗的抗化疗的驱动力 显着降低了疾病卵巢结果中的种族差异。