Project 1 Rabadan

项目1 拉巴丹

基本信息

批准号：
10394194
负责人：
Raul Rabadan
金额：
$ 35.23万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-08 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10394194
关键词：
Address Automobile Driving BARD1 gene BRCA mutations BRCA1 Mutation BRCA1 gene Biological Biology Breast Cancer Patient Cells Characteristics Chromosomal translocation Complex Computer Analysis DNA DNA Double Strand Break DNA Repair DNA Repair Gene DNA lesion Defect Development Double Strand Break Repair Family Foundations Genes Genome Genome Stability Genomic Instability Genomics Hereditary Breast Carcinoma Human Impairment Lesion Link Machine Learning Malignant Neoplasms Methods Methylation Missense Mutation Molecular Molecular Biology Mus Mutate Mutation PARP inhibition Pathogenicity Pathway interactions Patients Pattern Phenotype Process Proteins Risk Assessment Series Source Techniques Testing Tumor Suppression Tumor Suppressor Proteins Variant base blind brca gene cancer genome cancer initiation cancer subtypes computer framework de novo mutation driving force genome integrity genomic data genotoxicity human data improved in vivo malignant breast neoplasm mouse model mutant novel preservation promoter repaired triple-negative invasive breast carcinoma tumor tumor progression tumorigenesis whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT: Large-scale genomic studies of human tumors have uncovered a series of characteristic “mutation signatures”; i.e., statistically enriched patterns of DNA substitutions and rearrangements common across tumors. While some of these signatures are associated with particular cancer subtypes, known genotoxic insults, and/or rough mutational patterns arising from specific DNA repair defects, most remain uncharacterized without known biological correlates. To determine the mechanisms by which mutation signatures arise, we will initially focus on triple-negative breast cancers (TNBCs) with lesions in the BRCA1 tumor suppressor pathway. Recent studies have identified at least five distinct mutation signatures in TNBCs. However, we do not know if additional signatures exist, nor do we understand the molecular mechanisms by which these signatures are generated. BRCA1 acts to preserve genome integrity through multiple processes, including homology-directed repair (HDR) and stalled fork protection (SFP), and it does so in association with a number of distinct protein partners. Thus, the mutation signatures associated with TNBC may reflect the loss of particular BRCA1 pathway functions and/or defects in other as yet unidentified DNA repair factors. To address these issues, we will combine expertise in computation analysis of genomic data and the molecular biology of DNA repair to 1) elucidate the molecular mechanisms responsible for TNBC mutation signatures, and 2) determine the full spectrum of mutation signatures associated with TNBC patients bearing pathogenic lesions in the BRCA1 pathway.

项目摘要/摘要：人类肿瘤的大规模基因组研究发现了一系列特征性的“突变特征”。即，在肿瘤之间常见的DNA取代和重排的统计富集模式。尽管其中一些特征与特定的癌症亚型，已知的遗传毒性感染和/或由特定的DNA修复缺陷引起的粗糙突变模式，大多数没有表征已知的生物学相关。为了确定突变签名的机制，我们最初将专注于BRCA1肿瘤抑制途径中有病变的三阴性乳腺癌（TNBC）。最近的研究已经确定了TNBC中至少五个不同的突变特征。但是，我们不知道是否存在其他签名，我们也不了解这些签名是的分子机制生成。 BRCA1通过多个过程（包括同源性指导）来保护基因组完整性维修（HDR）和停滞的叉子保护（SFP），并且与许多不同的蛋白质相关合作伙伴。这就是与TNBC相关的突变特征可能反映了特定BRCA1的丧失途径在其他尚未确定的DNA修复因子中的功能和/或缺陷。为了解决这些问题，我们将在基因组数据的计算分析和DNA修复的分子生物学方面结合专业知识至1）阐明负责TNBC突变特征的分子机制，2）确定完整的与BRCA1中具有致病性病变的TNBC患者相关的突变特征频谱路径。