FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits

Abstract

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

Expanding the molecular signatures of malignant ossifying fibromyxoid tumours with two novel gene fusions: PHF1::FOXR1 and PHF1::FOXR2

“…FOXR1 has been implicated as an important factor in normal brain development in humans and mice, 14 and several human cancers show FOXR1 alterations, including B‐cell lymphoma and neuroblastoma 15,16 . Less is known about the developmental role of FOXR2 , but it too has been implicated in a wide range of human cancers, including the recently described entity, “CNS neuroblastoma, FOXR2 ‐activated” 17,18 . The PFH1:FOXR2 fusion identified in Case 2 is comprised of a fusion between exon 11 of the PHF1 gene and 5′ UTR of FOXR2 .…”

“…15,16 Less is known about the developmental role of FOXR2, but it too has been implicated in a wide range of human cancers, including the recently described entity, "CNS neuroblastoma, FOXR2activated". 17,18 The PFH1:FOXR2 fusion identified in Case 2 is comprised of a fusion between exon 11 of the PHF1 gene and 5 0 UTR of FOXR2. This fusion causes inframe change, adding exon 11 of PFH1 to exon 1 of FOXR2.…”

Current Open Trials and Molecular Update for Pediatric Embryonal Tumors

“…Additional genetic alterations include Chr.1q gain, CHr.16q loss, and Chr.8 gain, and most tumors were shown to overexpress the FOXR2 gene. The oncogenic mechanism behind FOXR2 overexpression is yet to be fully elucidated, but recent studies suggest that it plays a role in stabilizing MYCN as well as interacting with the ETS family of transcription factors [[46], [47]].…”

Pediatric Glioma Models Provide Insights into Tumor Development and Future Therapeutic Strategies

“…This model was used to evaluate the treatment efficacy of everolimus with dasatinib, which led to first-in-human studies of the combined treatment [52]. Models carrying PDGFRA D842V were also used to evaluate cannabidiol to target ID1 expression in DMG, the role of FOXR2 as a pan-cancer oncogene, vulnerabilities to MDM2 inhibition in tumors expressing PPM1D truncation, and the pro-tumorigenic role of ATRX loss and ATRX-associated vulnerabilities [50, 53, 129, 130]. However, it is important to note that the PDGFRA D842V mutation is not as common in glioma patients as focal amplification of the wild-type gene, and as this mutation is potently oncogenic on its own, its presence may eclipse the roles of other partner alterations [17].…”