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: 10490387
• 负责人: Shailja Pathania
• 金额: $ 5.8万
• 依托单位: UNIVERSITY OF MASSACHUSETTS BOSTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490387
• 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。前列腺腺癌是最常见的癌症类型之一