Identification of novel prostate cancer drivers using RegNetDriver: a framework for integration of genetic and epigenetic alterations with tissue-specific regulatory network

Dhingra, Priyanka; Martínez-Fundichely, Alexander; Berger, Adeline; Huang, Franklin W.; Forbes, Andre Neil; Liu, Eric Minwei; Liu, De Li; Sboner, Andrea; Tamayo, Pablo; Rickman, David S.; Rubin, Mark A.; Khurana, Ekta

doi:10.1186/s13059-017-1266-3

Cited by 31 publications

(25 citation statements)

References 123 publications

(210 reference statements)

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“…In this context, while acknowledging that teratomas are a special tumor type, our data suggest that cancer cells might even be able to bypass RAS nullyzygosity through the inactivation of suppressors such as ERF. Interestingly, recurrent deletions and inactivating mutations of ERF have been found recently in prostate cancer (Bose et al 2017;Dhingra et al 2017;Huang et al 2017). However, the impact of these mutations is still not fully characterized.…”

Section: Discussionmentioning

confidence: 99%

ERF deletion rescues RAS deficiency in mouse embryonic stem cells

et al. 2018

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MEK inhibition in combination with a glycogen synthase kinase-3β (GSK3β) inhibitor, referred as the 2i condition, favors pluripotency in embryonic stem cells (ESCs). However, the mechanisms by which the 2i condition limits ESC differentiation and whether RAS proteins are involved in this phenomenon remain poorly understood. Here we show that RAS nullyzygosity reduces the growth of mouse ESCs (mESCs) and prohibits their differentiation. Upon RAS deficiency or MEK inhibition, ERF (E twenty-six 2 [Ets2]-repressive factor), a transcriptional repressor from the ETS domain family, translocates to the nucleus, where it binds to the enhancers of pluripotency factors and key RAS targets. Remarkably, deletion of rescues the proliferative defects of RAS-devoid mESCs and restores their capacity to differentiate. Furthermore, we show that loss enables the development of RAS nullyzygous teratomas. In summary, this work reveals an essential role for RAS proteins in pluripotency and identifies ERF as a key mediator of the response to RAS/MEK/ERK inhibition in mESCs.

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Section: Discussionmentioning

confidence: 99%

ERF deletion rescues RAS deficiency in mouse embryonic stem cells

et al. 2018

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“…Fifth, the algorithm SEPIRA, which was used to construct the tissue-specific regulatory network and estimation of TF binding activity, is of a general nature and could be applied to any tissue type present in the GTEX database. The ability to infer regulatory activity from a DNAm profile further opens up its application to EWAS and cancer epigenome studies, offering a complementary approach to other recent methods [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Systems-epigenomics inference of transcription factor activity implicates aryl-hydrocarbon-receptor inactivation as a key event in lung cancer development

2017

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BackgroundDiverse molecular alterations associated with smoking in normal and precursor lung cancer cells have been reported, yet their role in lung cancer etiology remains unclear. A prominent example is hypomethylation of the aryl hydrocarbon-receptor repressor (AHRR) locus, which is observed in blood and squamous epithelial cells of smokers, but not in lung cancer.ResultsUsing a novel systems-epigenomics algorithm, called SEPIRA, which leverages the power of a large RNA-sequencing expression compendium to infer regulatory activity from messenger RNA expression or DNA methylation (DNAm) profiles, we infer the landscape of binding activity of lung-specific transcription factors (TFs) in lung carcinogenesis. We show that lung-specific TFs become preferentially inactivated in lung cancer and precursor lung cancer lesions and further demonstrate that these results can be derived using only DNAm data. We identify subsets of TFs which become inactivated in precursor cells. Among these regulatory factors, we identify AHR, the aryl hydrocarbon-receptor which controls a healthy immune response in the lung epithelium and whose repressor, AHRR, has recently been implicated in smoking-mediated lung cancer. In addition, we identify FOXJ1, a TF which promotes growth of airway cilia and effective clearance of the lung airway epithelium from carcinogens.ConclusionsWe identify TFs, such as AHR, which become inactivated in the earliest stages of lung cancer and which, unlike AHRR hypomethylation, are also inactivated in lung cancer itself. The novel systems-epigenomics algorithm SEPIRA will be useful to the wider epigenome-wide association study community as a means of inferring regulatory activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1366-0) contains supplementary material, which is available to authorized users.

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“…Current tools designed to identify non-coding drivers are based on mutation recurrence within regulatory elements (Juul, et al, 2017; Lochovsky, et al, 2015), predicted functional impact of somatic mutations (Mularoni, et al, 2016), or a combination of these approaches (Dhingra, et al, 2017; Hornshoj, et al, 2018). However, existing methods are designed to explore mutations within defined regulatory regions, such as promoters, enhancers or UTRs, therefore ignoring the rest of the non-coding genome.…”

Section: Introductionmentioning

confidence: 99%