Molecular Tumorigenesis of Bladder Cancer

总体：项目摘要 在过去三十年中，在美国最流行的癌症中，膀胱癌（BC） 每年的发病率一直排在第五位，每例的医疗费用一直排在第一位。尽管 由于其高患病率和惊人的医疗费用，BC直到最近才成为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，很少有测定和生物标志物存在， 可靠地诊断BC并预测其进展，并且很少有新的治疗方法可用于 有效管理BC。使这一点更加复杂的是，不列颠哥伦比亚省是高度异质性的主要组成部分， 表型变异和分子亚型，如先前的遗传研究和最近的整体研究所证明的那样， 基因组/外显子组/转录组分析。在过去的五年里，我们的PO 1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的生物基础问题 异质性，并取得了重大进展：辨别主要BC的组合遗传驱动因素 变异;建立DNA损伤和修复作为不同类型BC的区别特征;建立 XIAP作为BC侵袭的关键驱动因素;以及鉴定尿路上皮亚群作为BC侵袭的潜在祖细胞。 BC变体。这一更新应用程序建立在这一前进的势头，并侧重于更深层次的， 扩展的科学主题-BC的遗传，致癌，分子和细胞基础 通过提出几个重要的新问题来解决异质性问题。什么决定了主要BC变体的起源： 不同的遗传驱动因素与不同的祖细胞（项目1; P1）？这些亚硝胺是从 宿主细胞内电子烟蒸汽中的尼古丁导致肌肉侵入性BC以及它们如何影响尿路上皮DNA 损坏和修复（P2）？是否有一个主开关驱动基底亚型肌肉的形成， 侵入性BC（P3）？这一高度协调、协作的团队努力的结果应有助于 在我们对BC异质性的生物学基础的理解上取得了飞跃，导致了 新的生物标志物和治疗方法，为这种高度流行，但研究非常不足的疾病。

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.