The retinoblastoma tumor suppressor gene (RB1) plays a critical role in coordinating multiple pathways that impact cancer initiation, disease progression, and therapeutic responses. Here we probed molecular features associated with the RB-pathway across 31 tumor-types. While the RB-pathway has been purported to exhibit multiple mutually exclusive genetic events, only RB1 alteration is mutually exclusive with deregulation of CDK4/6 activity. An ER+ breast cancer model with targeted RB1 deletion was used to identify signatures of CDK4/6 activity and RB-dependency (CDK4/6-RB integrated signature). This signature was prognostic in tumor-types with gene expression features indicative of slower growth. Single copy loss on chromosome 13q encompassing the RB1 locus is prevalent in many cancers, yielding reduced expression of multiple genes in cis, and is inversely related to the CDK4/6-RB integrated signature supporting a cause-effect relationship. Genes that are positively and inversely correlated with the CDK4/6-RB integrated signature define new tumor-specific pathways associated with RB-pathway activity.

中文翻译：

---

RB肿瘤抑制途径的全癌分子分析。

视网膜母细胞瘤抑癌基因（RB1）在协调影响癌症发生，疾病进展和治疗反应的多种途径中起着关键作用。在这里，我们探讨了与跨越31种肿瘤类型的RB途径相关的分子特征。尽管据称RB途径表现出多个相互排斥的遗传事件，但只有RB1改变与CDK4 / 6活性的失控是相互排斥的。具有靶向RB1缺失的ER +乳腺癌模型用于鉴定CDK4 / 6活性和RB依赖性的特征（CDK4 / 6-RB整合特征）。该标志在具有基因表达特征的肿瘤类型中是预后性的，其指示生长较慢。围绕RB1基因座的13q染色体上的单拷贝丢失在许多癌症中十分普遍，导致顺式中多个基因的表达降低，与支持因果关系的CDK4 / 6-RB集成签名成反比。与CDK4 / 6-RB整合签名正相关和反相关的基因定义了与RB通路活性相关的新的肿瘤特异性通路。