Abstract 1833: Transcriptome characterization of high grade serous and endometrioid epithelial ovarian cancer tumors
Authors: Fridley Brooke L. , Dai Junqiang , Raghavan Rama , Wang Chen , Lu Pengcheng , Winham Stacey , Earp Madalene , Lawrenson Kate , Gayther Simon A. , Kalli Kimberly R. , Goode Ellen L. 
Published: July 2016

Background: Little transcriptomic research has compared epithelial ovarian cancer (EOC) histological subtypes. We set out to characterize the transcriptomes of high-grade serous carcinomas (HGSC) and endometrioid carcinomas (EC), which make up around 70% and 20% of EOC tumors, respectively, and have some histopathological similarities.

Methods: Fresh frozen tumors from EOC patients seen at the Mayo Clinic (30 EC and 62 HGSC) were used. 1ug RNA riboZero was used for library preparation using the Illumina TruSeq kit and sequenced on a HiSeq 2000 machine. Reads were aligned using TopHat2 followed by quantification of abundances using RSEM and differential expression analysis with edgeR. We analyzed transcriptomes, conducted pathway analyses, and summarized key candidate gene sets. Expressed SNVs (eSNVs) from the RNA-seq data were determined using GATK and RVboost.

Results: The analysis found 699 genes with FDR &lt; 1×10-5 for differential expression between HGSC and EC, with most genes being up-regulated in EC. The top most associated genes were TPH1, MAP2K6, KLK2, ADAM23, TESC and TRAF3IP2 (p&lt;10-22). Pathway analysis of the genes up-regulated in EC revealed enrichment of the “basal cell carcinoma signaling pathway” (p = 1.2×10-5). Within 1 Mb of the 25 known EOC risk loci, we observed higher expression in HGSC for RSPO1 and HPSE (p &lt;5×10-7). For genes functionally related to EOC, we observed in HGSC up-regulation (*p &lt; 10-5, ⁁p&lt;0.003) for FOXM1⁁, CDKN2A⁁, CCNE1*, CCND2⁁, PIK3CA*, BRCA2⁁, BIRC5⁁, MMP9⁁, FANCD2⁁, and MAML2⁁. In contrast, we found up-regulation in EC for MDM2*, KLK4*, BCL2⁁, CCND1*, ANXA4*, CDH1⁁, MMP7⁁, and MAML3⁁. We also identified 204 eSNVs (44 non-synonymous) associated with EC v HGSC subtype (p&lt;10-4); this included an exonic TRAF3IP2 eSNV (66% EC, 13% HGSC, p = 4×10-7, chr6:111877117).

Discussion: Using one of the largest sets of identically processed fresh-frozen EOC tumors, some patterns emerged among the numerous EC v HGSC transcriptomic differences. TPH1, up-expressed in EC, is regulated by SOX4 which was also up-regulated in EC. Two sets of genes related to Kallikreins serine proteases were differentially expressed, including KLK2 which is known to regulate EGFR and pro-inflammatory cytokines and is regulated by MYC. Lastly, TRAF3IP2 encodes for a protein involved in regulating cytokines through members of the NFKB pathway.

Conclusions: These findings suggest important biological insights into one of the rarer EOC histologies and may aid in the development of targeted treatment options. Research is on-going to incorporate additional features (e.g., DNA methylation, copy number) into a “systems biology” framework to better understand the molecular differences between EOC histologies.

Citation Format: Brooke L. Fridley, Junqiang Dai, Rama Raghavan, Chen Wang, Pengcheng Lu, Stacey Winham, Madalene Earp, Kate Lawrenson, Simon A. Gayther, Kimberly R. Kalli, Ellen L. Goode. Transcriptome characterization of high grade serous and endometrioid epithelial ovarian cancer tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1833.