Deep Quantitative Proteomics Identifies Conserved Proteome Alterations in Low and High-Grade Serous Ovarian Cancers

Abstract

Low-grade serous ovarian carcinoma (LGSOC) is a rare and largely chemoresistant subtype of epithelial ovarian cancer. Unlike treatment for high-grade serous ovarian cancer (HGSOC), management options for LGSOC patients are limited, in part, due to a lack of deep molecular characterization of this disease. To address this limitation, we performed quantitative mass spectrometry-based proteomic analyses of whole tissue collections of tumors harvested from LGSOC (n=12) and HGSOC (n=24) patients or normal fallopian tube tissues (n=12) from women with benign disease. We quantified 7,043 proteins across all patient samples and unsupervised analyses revealed proteome alterations distinctly stratify fallopian tube tissue, LGSOC, and HGSOC tumors. Proteins elevated in LGSOC compared to HGSOC tumors (LIMMA adjusted p < 0.05) were enriched for pathways regulating cilium assembly and included a pathway regulating activation of FAK1 by MET, a therapeutic target in LGSOC. Using data from an independent proteomic analysis of LGSOC (n=14) and HGSOC (n=30) tumors, we identified 330 co-altered proteins between LGSOC and HGSOC tumors exhibiting high quantitative correlation (Spearman Rho = 0.803, P < 2.2E10-16). Among these, MUC16 was identified as significantly elevated (>1.7 log2-fold) in LGSOC versus HGSOC. Immunohistochemistry analysis of MUC16 verified the increased abundance in LGSOC tissues and identified that MUC16 staining patterns in LGSOC are uniquely apical compared to HGSOC (Fishers Exact p = 0.001). Our deep proteomic analyses identifies highly-conserved proteome alterations distinguishing LGSOC from HGSOC tumors, including candidates regulating FAK1 signaling as well as a novel identification that MUC16 is elevated and exhibits an apical staining pattern in LGSOC tumors. These findings deepen our molecular understanding of LGSOC and provide unique insights into the regulation of MUC16 in LGSOC tumors.