Human cancers display a restricted set of expression profiles, despite diverse mutational drivers. This has led to the hypothesis that select sets of transcription factors act on similar target genes as an integrated network, buffering a tumor’s transcriptional state. Noninvasive papillary urothelial carcinoma (NIPUC) with higher cell cycle activity has higher risk of recurrence and progression. In this paper, we describe a transcriptional network of cell cycle dysregulation in NIPUC, which was delineated using the ARACNe algorithm applied to expression data from a new cohort (n = 81, RNA sequencing), and two previously published cohorts. The transcriptional network comprised 121 transcription factors, including the pluripotency factors SOX2 and SALL4, the sex hormone binding receptors ESR1 and PGR, and multiple homeobox factors. Of these 121 transcription factors, 65 and 56 were more active in tumors with greater and less cell cycle activity, respectively. When clustered by activity of these transcription factors, tumors divided into High Cell Cycle versus Low Cell Cycle groups. Tumors in the High Cell Cycle group demonstrated greater mutational burden and copy number instability. A putative mutational driver of cell cycle dysregulation, such as homozygous loss of CDKN2A, was found in only 50% of High Cell Cycle NIPUC, suggesting a prominent role of transcription factor activity in driving cell cycle dysregulation. Activity of the 121 transcription factors strongly associated with expression of EZH2 and other members of the PRC2 complex, suggesting regulation by this complex influences expression of the transcription factors in this network. Activity of transcription factors in this network also associated with signatures of pluripotency and epithelial-to-mesenchymal transition (EMT), suggesting they play a role in driving evolution to invasive carcinoma. Consistent with this, these transcription factors differed in activity between NIPUC and invasive urothelial carcinoma.

尽管突变驱动因素不同，但人类癌症却表现出一组有限的表达谱。这导致了这样的假设：选定的转录因子组作为一个集成网络作用于相似的靶基因，缓冲肿瘤的转录状态。细胞周期活性较高的非浸润性乳头状尿路上皮癌（NIPUC）复发和进展的风险较高。在本文中，我们描述了 NIPUC 中细胞周期失调的转录网络，该网络是使用 ARACNe 算法描绘的，该算法应用于新队列（n = 81，RNA 测序）和两个先前发表的队列的表达数据。转录网络由 121 个转录因子组成，包括多能性因子 SOX2 和 SALL4、性激素结合受体 ESR1 和 PGR 以及多种同源盒因子。在这 121 个转录因子中，分别有 65 个和 56 个在细胞周期活性较高和较低的肿瘤中更加活跃。当根据这些转录因子的活性进行聚类时，肿瘤分为高细胞周期组和低细胞周期组。高细胞周期组中的肿瘤表现出更大的突变负担和拷贝数不稳定。仅在 50% 的高细胞周期 NIPUC 中发现了细胞周期失调的假定突变驱动因素，例如CDKN2A的纯合缺失，这表明转录因子活性在驱动细胞周期失调中发挥着重要作用。 121 个转录因子的活性与 EZH2 和 PRC2 复合体其他成员的表达密切相关，表明该复合体的调节影响该网络中转录因子的表达。 该网络中转录因子的活性也与多能性和上皮间质转化（EMT）的特征相关，表明它们在驱动侵袭性癌的进化中发挥着作用。与此一致的是，这些转录因子在 NIPUC 和浸润性尿路上皮癌之间的活性不同。