LAUSR

There is an emerging consensus that a majority of high-grade serous carcinomas, the most common type of ovarian cancer, are derived from PAX8-expressing cells in the distal fallopian tube. Careful histologic examination of fallopian tubes from BRCA1/2 mutation carriers has led to the identification of a morphological continuum that begins with a benign secretory cell, transitions to identifiable precursor lesions, and culminates in serous carcinoma. We have previously demonstrated the biologic plausibility of this hypothesis by showing that dysregulation of BRCA1/2 and TP53 in PAX8-expressing mouse or human fallopian tube secretory epithelial cells (FTSECs) can induce tumors that are genomically and phenotypically identical to human high-grade serous ovarian cancers. While PAX8 serves as the basis for many of the fallopian tube-based models we have developed, little is known about its role during neoplastic transformation. PAX8 is a lineage-defining transcription factor that directs the development of the Mullerian duct (the female reproductive tract). Its expression is retained by nearly all high-grade serous carcinomas but it remains unknown whether alterations in the PAX8 cistrome contribute to ovarian carcinomas. Using whole transcriptome shotgun sequencing (RNA-Seq) after PAX8 knockdown and ChIP-Seq, we show that FTSECs and high-grade serous carcinomas are distinguished by marked reprogramming of the PAX8 cistrome. Interestingly, the majority of PAX8 binding peaks are found in intronic and intergenic regions of the genome rather than promoters. Genes that are significantly altered between FTSECs and carcinoma lines are enriched near PAX8 binding sites. These sites are also near TEAD binding sites, and these transcriptional changes may be related to PAX8 interactions with the TEAD/YAP1 signaling pathway. These data suggest that transcriptional changes after transformation in ovarian cancer are closely related to epigenetic remodeling in lineage-specific transcription factors. Citation Format: Ronny Drapkin. STARING DOWN THE BARREL OF A TUBE AT THE ORIGINS OF OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr KP02.