Project 1 Rabadan

项目总结/摘要： 对人类肿瘤的大规模基因组研究揭示了一系列特征性的“突变特征”; 也就是说，在肿瘤中常见的DNA置换和重排的统计学富集模式。而 这些特征中的一些与特定的癌症亚型、已知的遗传毒性损伤和/或 由特定DNA修复缺陷引起的粗略突变模式，大多数仍然没有特征， 已知的生物学相关性。为了确定突变签名产生的机制，我们将首先 重点关注BRCA 1肿瘤抑制通路病变的三阴性乳腺癌（TNBC）。最近 研究已经在TNBC中鉴定出至少五种不同的突变特征。然而，我们不知道， 存在额外的签名，我们也不了解这些签名的分子机制， 生成的. BRCA 1通过多个过程，包括同源性定向， 修复（HDR）和失速叉保护（SFP），并且它与许多不同的蛋白质相关 伙伴因此，与TNBC相关的突变特征可能反映了特定BRCA 1基因的缺失。 途径功能和/或其他尚未鉴定的DNA修复因子的缺陷。为了解决这些问题，我们 将结合联合收割机在基因组数据的计算分析和DNA修复的分子生物学方面的专业知识， 阐明负责TNBC突变特征的分子机制，以及2）确定完整的 与携带BRCA 1致病性病变的TNBC患者相关的突变特征谱 通路

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.