Mechanisms Underlying Replication Stress And Genome Instability Upon BRCA2 Deficiency

BRCA2 缺陷引起的复制压力和基因组不稳定的潜在机制

基本信息

批准号：
10504242
负责人：
Shailja Pathania
金额：
$ 34.88万
依托单位：
UNIVERSITY OF MASSACHUSETTS BOSTON
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：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10504242
关键词：
Address Affect Applications Grants Automobile Driving BRCA2 Mutation BRCA2 gene Biological Markers Breast Cancer Risk Factor Cells Chemoresistance Climacteric Combination Drug Therapy Cytosine Cytosine deaminase DNA DNA Damage DNA Sequence Alteration DNA replication fork Data Deaminase Deamination Defect Down-Regulation Enzymes Event Family Genome Genome Stability Genomic Instability Genomics Germ-Line Mutation Goals Incidence Individual Knowledge Lead Learning Location Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Mammary Gland Parenchyma Molecular Normal Cell Nucleotide Excision Repair Operative Surgical Procedures Ovarian Tissue Pancreas Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Prevention strategy Process Prostate Publishing Risk Role Single-Stranded DNA Site Somatic Mutation Source Testing Therapeutic Time Tissues Treatment Efficacy Uracil Woman Work Xenograft Model base cancer prevention chemotherapy design efficacy evaluation exhaustion experimental study high risk insight lifetime risk malignant breast neoplasm mutant mutation carrier neoplastic cell novel novel therapeutic intervention potential biomarker prophylactic repaired replication factor A replication stress tool tumor tumorigenesis variant of unknown significance

项目摘要

PROJECT SUMMARY BRCA2 mutation carriers are highly predisposed to breast and ovarian cancer (60% risk for breast cancer and 30-40% for ovarian cancer), and also have increased risk for other cancers like prostate and pancreatic. However, the mechanisms underlying these phenomena are still poorly understood. The molecular pathogenic steps, especially the earliest ones that drive the transition of normal cells (BRCA2mut/+) in a BRCA2 mutation carrier to tumor cells are largely unknown. Experiments detailed in this proposal will provide valuable clues to what those early steps could be. The knowledge and understanding of the way a normal, presumably healthy cell in BRCA2 mutation carrying individual starts becoming a tumor cell, will give us a much-needed early advantage to help design preventive strategies and contribute towards decreasing B2 mutant cancer incidence. The experimental strategy described in this proposal is based on our recently published work that shows increased single stranded DNA (ssDNA) accumulation in BRCA2 deficient cells, and on our preliminary data that shows high abasic site and uracil accumulation in BRCA2 deficient cells. Our preliminary data also shows defective nucleotide excision repair (NER) pathway in BRCA2 deficient cells. Based on our strong preliminary data, we propose to study the role of APOBEC/AID family of cytosine deaminases in generating abasic sites in BRCA2 deficient cells. We will also use BRCA2 patient derived tissue to design new ways to classify variants of unknown significance and also learn how increased abasic site and uracil in B2 heterozygous cells could contribute to genomic instability and tumorigenesis. Finally, we will also study whether BRCA2 deficient cells are defective in NER when undergoing replication stress, and if this weakness in BRCA2 mutant tumors could be targeted by combination drug therapy. This study provides an opportunity to address the question of early DNA damaging events that drive BRCA2 mutant tumorigenesis, and has the potential to provide the much needed, critical information that will help with the design of effective cancer prevention and therapeutic strategies for BRCA2 mutation bearing women.

项目概要 BRCA2 突变携带者极易患乳腺癌和卵巢癌（乳腺癌和卵巢癌的风险为 60%）卵巢癌的风险为 30-40%），并且患前列腺癌和胰腺癌等其他癌症的风险也增加。然而，这些现象背后的机制仍然知之甚少。分子致病性步骤，尤其是在 BRCA2 突变中驱动正常细胞 (BRCA2mut/+) 转变的最早步骤肿瘤细胞的载体尚不清楚。本提案中详细的实验将为以下问题提供有价值的线索：这些早期步骤可能是什么。对正常的、大概健康的方式的认识和理解携带BRCA2突变的个体开始变成肿瘤细胞，将为我们提供急需的早期发现有助于设计预防策略并有助于降低 B2 突变癌症发病率。本提案中描述的实验策略基于我们最近发表的工作，该工作表明 BRCA2 缺陷细胞中单链 DNA (ssDNA) 积累增加，根据我们的初步数据显示 BRCA2 缺陷细胞中脱碱基位点和尿嘧啶的高积累。我们的初步数据还显示 BRCA2 缺陷细胞中的缺陷核苷酸切除修复 (NER) 途径。基于我们强大的前期准备数据，我们建议研究胞嘧啶脱氨酶 APOBEC/AID 家族在产生脱碱基位点中的作用 BRCA2 缺陷细胞。我们还将使用 BRCA2 患者来源的组织来设计新的方法来对 BRCA2 变异进行分类未知的意义，并了解 B2 杂合细胞中脱碱基位点和尿嘧啶的增加如何可能导致基因组不稳定和肿瘤发生。最后，我们还将研究BRCA2缺陷细胞是否当经历复制应激时，NER 存在缺陷，如果 BRCA2 突变肿瘤中的这种缺陷可能是以联合药物治疗为目标。这项研究提供了一个机会来解决驱动早期 DNA 损伤事件的问题 BRCA2 突变体肿瘤发生，并有可能提供急需的关键信息，帮助设计针对 BRCA2 突变的有效癌症预防和治疗策略女性。