Project 1 Rabadan

项目摘要/摘要： 对人类肿瘤的大规模基因组研究揭示了一系列具有特征的“突变特征”； 即，在肿瘤中常见的DNA替换和重排的统计丰富模式。而当 其中一些特征与特定的癌症亚型、已知的基因毒性侮辱和/或 由特定DNA修复缺陷引起的粗略突变模式，大多数仍未表现出特征 已知的生物相关性。为了确定突变签名产生的机制，我们首先将 重点关注BRCA1抑癌基因通路中有病变的三阴性乳腺癌(TNBCs)。近期 研究已经确定了TNBCs中至少五个不同的突变特征。然而，我们不知道是否 更多的签名存在，我们也不了解这些签名的分子机制 已生成。BRCA1通过多个过程来保持基因组的完整性，包括同源性导向的过程 修复(HDR)和失速的叉子保护(SFP)，它与许多不同的蛋白质相关 合伙人。因此，与TNBC相关的突变签名可以反映特定BRCA1的丢失 其他尚未确定的DNA修复因子的通路功能和/或缺陷。为了解决这些问题，我们 将把基因组数据的计算分析和DNA修复的分子生物学的专业知识结合到1) 阐明导致TNBC突变特征的分子机制，以及2)确定完整的 与携带BRCA1致病病变的TNBC患者相关的突变特征谱 路径。

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.