Forkhead box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and pediatric cancer samples and found FOXR2 to be aberrantly upregulated in 70% of all cancer types and 8% of all individual tumors. The majority of tumors (78%) aberrantly expressed FOXR2 through a previously undescribed epigenetic mechanism that involves hypomethylation of a novel promoter, which was functionally validated as necessary for FOXR2 expression and proliferation in FOXR2-expressing cancer cells. FOXR2 promoted tumor growth across multiple cancer lineages and co-opted ETS family transcription circuits across cancers. Taken together, this study identifies FOXR2 as a potent and ubiquitous oncogene that is epigenetically activated across the majority of human cancers. The identification of hijacking of ETS transcription circuits by FOXR2 extends the mechanisms known to active ETS transcription factors and highlights how transcription factor families cooperate to enhance tumorigenesis. Significance: This work identifies a novel promoter that drives aberrant FOXR2 expression and delineates FOXR2 as a pan-cancer oncogene that specifically activates ETS transcriptional circuits across human cancers. See related commentary by Liu and Northcott, p. 2977

中文翻译：

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FOXR2 是一种表观遗传调控的泛癌癌基因，可激活 ETS 转录电路


叉头框 R2 (FOXR2) 是一种位于 X 染色体上的叉头转录因子，其表达通常仅限于睾丸。在这项研究中，我们对 10,000 多个成人和儿童癌症样本中的 FOXR2 激活进行了泛癌分析，发现 FOXR2 在 70% 的所有癌症类型和 8% 的所有个体肿瘤中异常上调。大多数肿瘤 (78%) 通过先前未描述的表观遗传机制异常表达 FOXR2，该机制涉及新型启动子的低甲基化，该启动子已被功能验证为 FOXR2 表达癌细胞中 FOXR2 表达和增殖所必需的。 FOXR2 促进多种癌症谱系的肿瘤生长，并在癌症中增选 ETS 家族转录回路。总而言之，这项研究将 FOXR2 确定为一种有效且普遍存在的癌基因，在大多数人类癌症中都通过表观遗传激活。 FOXR2 劫持 ETS 转录回路的鉴定扩展了活性 ETS 转录因子的已知机制，并强调了转录因子家族如何合作增强肿瘤发生。意义：这项工作鉴定了一种驱动异常 FOXR2 表达的新型启动子，并将 FOXR2 描述为一种泛癌癌基因，可特异性激活跨人类癌症的 ETS 转录回路。参见 Liu 和 Northcott 的相关评论，第 17 页。 2977