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Metadata Commons Identifier

HMC000065

Project Title

The Pathognomonic FOXL2 C134W Mutation Alters DNA-Binding Specificity

Project Description

<p>The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumours (AGCT) and a diagnostic marker for this tumour type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore the mechanisms driving FOXL2C134W pathogenicity we engineered V5-FOXL2 and V5-FOXL2C134W doxycycline inducible isogenic cell lines and performed ChIP-seq and transcriptome profiling following transgenic induction. Interestingly we found that FOXL2C134W associates with the majority of FOXL2 binding sites as well as a large collection of novel regions throughout the genome. Integrated analysis of FOXL2C134W specific proximal promoter binding sites and differential gene expression identified direct targets of FOXL2C134W. We validated one such target and demonstrated a FOXL2C134W dependent sensitivity to a therapeutic that targets survivin (YM155). Taken together our results suggest that FOXL2C134W pathogenicity in AGCT is driven in part by an alteration in DNA binding specificity contributing to an oncogenic transcriptional program.</p>

Project Funder(s)

Terry Fox Research Institute

Project Institution(s)

University of British Columbia, Canada's Michael Smith Genome Sciences Centre

Project Investigator(s)

Martin Hirst, Gregg B. Morin, David G. Huntsman

Data Access Request URL*

Keywords

FOXL2 transcription factor, adult-type granulosa cell tumors, ovary, cancer, epigenomics

Publication Link

https://pubmed.ncbi.nlm.nih.gov/32641414/

Study Completed

Cohort Name

Human Ovarian Granulosa Cells

Cohort Size

Disease/Condition Studied

granulosa cell tumor, cancer

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Biobanking Consent Available

Medical History Available

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Clinical Data Types Available

Time Course Data Points

0, 3, 6, 8, 12, 24 hours following doxycycline induction in SVOG3e cell line

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