Abstract GMM-042: PAN-CANCER TRANSCRIPTION FACTOR ANALYSES IDENTIFY ZNF217 AS A NOVEL DRIVER IN HGSOC
Authors: Nameki Robbin , Fonseca Marcos A. S. , Reddy Jessica , Vavra Kevin C. , Segato Felipe , Corona Rosario I. , Seo Ji-Heui , Liu Annie , Abbasi Forough , Lin Xianzhi , Karlan Beth Y. , Freedman Matthew L. , Gayther Simon A. , Noushmehr Houtan , Lawrenson Kate 
Published: June 2021

Ovarian cancer is a rare but highly lethal gynecologic malignancy, causing around 14,000 deaths annually in the US. The current standard of care for ovarian cancer includes a combination of surgical cytoreduction and platinum-based chemotherapy. Despite these aggressive treatments, most patients suffer from fatal relapses that indicate an urgent need for novel targeted therapies. Master Transcription Factors (MTFs) are transcriptional regulators responsible for cellular identity, and are associated with cell type specific regions of active chromatin termed super-enhancers (SEs). In cancer, MTFs are drivers of tumor development across a variety of organs, and MTF interfering therapies are one of the most successful therapies available today. To further identify tumor-specific MTFs, we have developed the ‘Cancer Core Transcription factor Specificity (CaCTS)' algorithm and prioritized MTFs from a pan-cancer cohort of 10,000 tumors profiled by RNA-sequencing. Results demonstrated that many tumor MTFs derived from CaCTS were specific to its normal tissue-type, validating the algorithm's ability to identify factors involved in cellular identity. On the other hand, a set of highly expressed TFs were frequently observed in multiple cancer types, indicating two distinct classes of MTFs: lineage-specific MTFs and pan-cancer MTFs.

In High-Grade Serous Ovarian Cancer (HGSOC), CaCTS prioritized 21 TFs with lineage specific MTF traits. All 21 candidate MTFs were highly expressed in primary HGSOC specimens and aligned with HGSOC SEs identified via H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq). As expected, WT1 and PAX8 were identified, transcription factors previously implicated to be essential in HGSOC lineage specificity. Our algorithm also identified ZNF217, a novel candidate MTF in HGSOC. ZNF217 plays a key role in breast cancer, a tumor type that shares many epidemiological, hormonal and genetic risk factors with HGSOC. Mining of a publicly available gene knockout experiment in 13 HGSOC cell lines revealed ZNF217 to have similar levels of gene essentiality as PAX8. We are currently examining the role of ZNF217 as a MTF in HGSOC by determining its target genes, binding partners, and cellular consequences of siRNA-mediated knockdown. We expect ZNF217 to occupy SEs that drive expression of genes critical for cell identity, co-occupy SEs with other candidate MTFs, and depletion of ZNF217 to result in loss of cell state. Understanding the mechanisms of transcriptional control in HGSOC will ultimately help to identify clinically relevant drivers which can serve as novel therapeutic targets for this devastating disease.

Citation Format: Robbin Nameki, Marcos A. S. Fonseca, Jessica Reddy, Kevin C. Vavra, Felipe Segato, Rosario I. Corona, Ji-Heui Seo, Annie Liu, Forough Abbasi, Xianzhi Lin, Beth Y. Karlan, Matthew L. Freedman, Simon A. Gayther, Houtan Noushmehr, Kate Lawrenson. PAN-CANCER TRANSCRIPTION FACTOR ANALYSES IDENTIFY ZNF217 AS A NOVEL DRIVER IN HGSOC [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-042.