We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term “forerunner” genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two of these genes, LPAR6 and CAB39L, are preferentially downregulated in the luminal and basal subtypes of bladder cancer, respectively. Their loss of function dysregulates urothelial differentiation, sensitizing the urothelium to N-butyl-N-(4-hydroxybutyl)nitrosamine-induced cancers, which recapitulate the luminal and basal subtypes of human bladder cancer.

我们描述了一种结合组织学和分子图谱的策略，该策略允许在整个器官范围内询问与癌症发展相关的变化的时间顺序。使用这种方法，我们展示了膀胱癌发展过程中RB1周围的改变序列。我们发现RB1不参与肿瘤前克隆的初始扩增。相反，我们发现了一组连续的基因，我们称之为“先行者”基因，其沉默与引发癌变的斑块样场效应的发展有关。具体来说，我们确定了映射在RB1附近的五个候选先行基因（ITM2B、LPAR6、MLNR、CAB39L和ARL11）。其中两个基因LPAR6和CAB39L分别在膀胱癌的管腔亚型和基底亚型中优先下调。它们的功能丧失会导致尿路上皮分化失调，使尿路上皮对 N-丁基-N-(4-羟丁基)亚硝胺诱导的癌症敏感，这概括了人类膀胱癌的管腔亚型和基底亚型。