DNA repair gene mutations and prostate cancer

DNA修复基因突变与前列腺癌

基本信息

批准号：
9883610
负责人：
BINGHUI SHEN
金额：
$ 71.68万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-02 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883610
关键词：
Androgen Receptor Androgens Antineoplastic Agents Biochemistry Biological Blood specimen Cancer Etiology Cancer Family Cell Culture Techniques Cell Cycle Checkpoint Cells Cellular biology Cities Collection Coupled DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder DNA Repair Gene DNA Repair Pathway Data Defect Development Disease susceptibility Double Strand Break Repair Early Diagnosis Ensure Evaluation Excision Family Gene Mutation Genetic Genetic Transcription Genome Stability Genomic Instability Germ-Line Mutation Goals Heritability Human Impairment In Vitro Inherited Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Medical center Missense Mutation Molecular Molecular Target Mus Mutate Mutation Nebraska Neoplastic Cell Transformation Nonhomologous DNA End Joining Oncogenic Pathway interactions Prostate Prostatic Receptor Signaling Regimen Research Risk Risk Estimate Risk Factors Role Sampling Site Specimen Stress Susceptibility Gene System Testing The Sun Therapeutic Tissues Topoisomerase Universities Validation Virulence Factors Work androgen sensitive base cancer genetics cancer initiation cancer risk castration resistant prostate cancer design drug development early detection biomarkers endonuclease exome sequencing experience experimental study gene product gene repair genetic approach genetic architecture genome integrity helicase inhibitor/antagonist innovation insight loss of function mouse genetics mouse model novel nuclease overexpression prevent prostate cancer risk prostate carcinogenesis protein function receptor expression recruit repaired response risk variant targeted sequencing tumor progression tumorigenesis

项目摘要

Prostate cancer (PCa) is one of the most heritable human cancers, with inherited risk estimates of up to 60%; however, the underlying inherited genetic architecture is still largely unexplained. Our unique access to a collection of 446 blood specimens from 211 PCa families has enabled an innovative family-based approach to identifying novel disease-susceptibility loci. To date, we have collected targeted sequencing data from a panel of 48 “cancer risk genes” using samples from all of the PCa families, and whole-exome sequencing (WES) data using samples from a subset of the PCa families. We identified 45 familial loss-of-function and missense mutations in 32 DNA damage response and repair genes. Most of these gene products are known to participate in homology-directed DNA repair (HDR), an error-free type of DNA double-strand break (DSB) repair. DSBs can result from androgen receptor (AR)-induced transcriptional stress and increase cancer risk in androgen- responsive tissues, such as the prostate. In response to androgen stimulation, both TOP2B topoisomerase and LINE-1 endonuclease are recruited to active transcription sites and induce DSBs. Accumulated evidence suggests that loss of HDR will promote other error-prone repair pathways, such as alternative non-homologous end joining, causing mutation accumulation and genomic instability. The mutations we have identified are all germline mutations, representing potential causal genetic factors. We therefore hypothesize that functional deficiency in the HDR pathway, due to loss-of-function and missense mutations in HDR genes, contributes to genomic instability and PCa. We have designed the following three specific aims to test our central hypothesis: 1) To determine the functional defects in DNA damage response and HDR caused by PCa-associated HDR gene mutations; 2) To define the roles of nucleases EXO5 and EXD2 and helicases HFM1 and FANCM in resecting DNA ends at AR-induced, TOP2B-linked DSBs for HDR in prostate cells; 3) To assess the biological significance of AR signaling and the HDR pathway in PCa tumorigenesis. Our strong research team includes Dr. Binghui Shen (contact PI, City of Hope [COH]) and Dr. Xiaochun Yu (mPI; COH), both experts in the fields of DNA damage repair and cancer genetics, and recognized PCa biologists Dr. Zijie Sun (mPI; COH) and Dr. Ming- Fong Lin (co-I; University of Nebraska Medical Center). We will test the role of HDR gene mutations as risk factors for PCa and define the underlying molecular mechanism(s) linking HDR gene mutations to illegitimate DNA repair and PCa development. Completion of the proposed work will significantly advance our understanding of the role of HDR in cancer, especially PCa. We will use an innovative approach to identify novel PCa-associated HDR defects based on familial inheritance and evaluation of both loss-of-function and missense mutations. These insights will impact the field by increasing the availability of biomarkers for early diagnosis and providing molecular targets for anti-cancer drug development.

前列腺癌 (PCa) 是最具遗传性的人类癌症之一，遗传风险估计高达 60%；然而，潜在的遗传基因结构在很大程度上仍然无法解释。从 211 个 PCa 家庭采集了 446 份血液样本，采用基于家庭的创新方法迄今为止，我们已经从一组中收集了目标测序数据。使用所有 PCa 家族的样本和全外显子组测序 (WES) 数据分析 48 个“癌症风险基因” 我们使用来自 PCa 家族子集的样本确定了 45 个家族性功能丧失和错义。已知 32 个 DNA 损伤反应和修复基因的突变参与其中。在同源定向 DNA 修复 (HDR) 中，可以进行无错误类型的 DNA 双链断裂 (DSB) 修复。雄激素受体（AR）诱导的转录应激导致雄激素增加癌症风险响应性组织，如前列腺，对雄激素刺激作出反应，TOP2B 拓扑异构酶和 LINE-1 核酸内切酶被招募到活性转录位点并诱导 DSB 积累。表明 HDR 的丢失将促进其他容易出错的修复途径，例如替代的非同源修复途径末端连接，导致突变积累和基因组不稳定。种系突变，代表潜在的致病遗传因素。由于 HDR 基因的功能丧失和错义突变，HDR 通路的缺陷导致我们设计了以下三个具体目标来检验我们的中心假设： 1) 确定PCa相关的HDR引起的DNA损伤反应和HDR的功能缺陷基因突变；2) 定义核酸酶 EXO5 和 EXD2 以及解旋酶 HFM1 和 FANCM 在切除 AR 诱导的 TOP2B 连接 DSB 处的 DNA 末端以实现前列腺细胞中的 HDR 3) 评估生物学效果； AR 信号传导和 HDR 通路在 PCa 肿瘤发生中的重要性我们强大的研究团队包括 Dr. Binghui Shen（联系人 PI，希望之城 [COH]）和于晓春博士（mPI；COH）都是以下领域的专家 DNA 损伤修复和癌症遗传学，并认可 PCa 生物学家 Zijie Sun 博士（mPI；COH）和 Ming 博士- Fong Lin（co-I；内布拉斯加大学医学中心）我们将测试 HDR 基因突变作为风险的作用。 PCa 的因素并定义将 HDR 基因突变与非法生育联系起来的潜在分子机制 DNA 修复和 PCa 开发的完成将显着增进我们的理解。我们将使用一种创新方法来新识别与 PCa 相关的 HDR 的作用。基于家族遗传的 HDR 缺陷以及功能丧失和错义突变的评估。这些见解将通过增加用于早期诊断的生物标志物的可用性并提供影响该领域抗癌药物开发的分子靶点。