Molecular Tumorigenesis of Bladder Cancer

总体情况：项目摘要 在过去的三十年里，膀胱癌是美国最常见的癌症之一。 在年发病率方面一直位居第五，在每个病例的医疗费用方面一直位居第一。尽管 不列颠哥伦比亚省的高患病率和惊人的医疗费用，直到最近还是研究最少的癌症之一 在基础、转化和临床研究方面的努力有限。因此，很少有分析和生物标志物存在于 可靠地诊断BC并预测其进展，几乎没有新的治疗方法可用来 有效管理卑诗省。雪上加霜的是，BC是高度异质的，由主要的 表型变异和分子亚型，如先前的遗传学研究和最近的整体- 基因组/外显子组/转录组分析。在过去的五年里，我们PO1团队的调查人员 以高度协同和协作的方式共同努力解决BC的生物学基础 异质性，并在以下方面取得了重大进展：识别主要BC的组合遗传驱动因素 变异体；确定DNA损伤和修复作为不同类型BC的区别特征；建立 XIAP是BC侵袭的关键驱动因素；并确定尿路上皮亚群为潜在的BC前体细胞 公元前的变种。此续订申请建立在这一前进势头的基础上，并专注于更深层次的 扩展的科学主题-BC的遗传、致癌、分子和细胞基础 异质性，通过提出几个重要的新问题。公元前主要变种的起源是什么(S)： 分化的遗传驱动因素与分化的祖细胞(项目1；P1)？亚硝胺是从 电子烟烟雾中的尼古丁在宿主细胞内引起肌肉侵袭性BC及其如何影响尿路上皮DNA 损坏和修复(P2)？有没有一个主开关来驱动基底型肌肉的形成- 侵袭性BC(P3)？这种高度协调、协作的团队努力的结果应该有助于主要 在我们对BC异质性的生物学基础的理解上的飞跃，导致了 针对这种高度流行但研究极少的疾病的新生物标志物和治疗方法。

Overall: Project Summary Of the most prevalent cancers in the United States over the last three decades, bladder cancer (BC) has consistently ranked the fifth in annual incidence and the first in medical expenses on a per-case basis. Despite its high prevalence and staggering medical costs, BC is until recently among the least studied cancers with limited efforts in basic, translational and clinical research. Consequently, few assays and biomarkers exist to reliably diagnose BC and predict its progression and few new therapeutic approaches are available to effectively manage BC. Compounding this is the fact that BC is highly heterogeneous comprised of major phenotypic variants and molecular subtypes, as evidenced by previous genetic studies and recent whole- genome/-exome/transcriptome analyses. Over the last five years, the investigators of our PO1 Team have worked together in a highly synergistic and collaborative manner in tackling the biological bases of BC heterogeneity and made significant strides in: discerning the combinatorial genetic drivers of major BC variants; establishing DNA damage and repair as distinguishing features of different types of BC; establishing XIAP as a critical driver of BC invasion; and identifying urothelial subpopulations as potential progenitor cells of BC variants. This renewal application builds on this forward momentum and focuses on a much deeper and expanded scientific theme – the genetic, carcinogenomic, molecular and cellular underpinnings of BC heterogeneity, by asking several important new questions. What dictates the origin(s) of major BC variants: divergent genetic drivers versus divergent progenitor cells (Project 1; P1)? Do the nitrosamines converted from nicotine in E-cigarette vapor within host cells cause muscle-invasive BC and how do they affect urothelial DNA damage and repair (P2)? And is there a master switch that drives the formation of basal-subtype muscle- invasive BC (P3)? Results from this highly coordinated, collaborative team effort should contribute to the major leap forward in our understanding of the biological bases of BC heterogeneity, leading to the development of novel biomarkers and therapeutics for this highly prevalent but extremely under-studied disease.