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Abstract
Objective: The biology of high grade serous ovarian carcinoma (HGSOC) is poorly understood. Little has been reported on intratumoral homogeneity or heterogeneity of primary HGSOC tumors and their metastases. We evaluated the global protein expression profiles of paired primary and metastatic HGSOC from formalin-fixed, paraffin-embedded (FFPE) tissue samples. Methods: After IRB approval, six patients with advanced HGSOC were identified with tumor in both ovaries at initial surgery. Laser capture microdissection (LCM) was used to extract tumor for protein digestion. Peptides were extracted and analyzed by reversed-phase liquid chromatography coupled to a linear ion trap mass spectrometer. Tandem mass spectra were searched against the UniProt human protein database. Differences in protein abundance between samples were assessed and analyzed by Ingenuity Pathway Analysis software. Immunohistochemistry (IHC) for select proteins from the original and an additional validation set of five patients was performed. Results: Unsupervised clustering of the abundance profiles placed the paired specimens adjacent to each other. IHC H-score analysis of the validation set revealed a strong correlation between paired samples for all proteins. For the similarly expressed proteins, the estimated correlation coefficients in two of three experimental samples and all validation samples were statistically significant (p < 0.05). The estimated correlation coefficients in the experimental sample proteins classified as differentially expressed were not statistically significant. Conclusion: A global proteomic screen of primary HGSOC tumors and their metastatic lesions identifies tumoral homogeneity and heterogeneity and provides preliminary insight into these protein profiles and the cellular pathways they constitute.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy [1]
Scans performed in the linear ion trap (LIT) where the seven most abundant peptide molecular ions were selected for collision-induced dissociation (CID), using a normalized collision energy of 35%
E-HGSOC: experimental high grade serous ovarian carcinoma samples; V-HGSOC: validation high grade serous ovarian carcinoma samples; The H-score is given as the sum of the percent staining multiplied by an ordinal value corresponding to the intensity level (0 = none, 1 = weak, 2 = moderate, 3 = strong)
Summary
The majority of patients with EOC present with metastatic lesions identified at primary surgery and experience recurrence This type of clinical behavior affords researchers the opportunity to evaluate multiple tumor samples throughout a patient’s clinical course. Attempts to identify serum biomarkers, investigations of the histologic types, and genomic studies of metastatic lesions have been completed utilizing fresh-frozen samples [5,6,7,8,9]. Proteomic studies utilized HGSOC tissue sources ranging from fresh-frozen specimens to ovarian cancer cell lines [13,22]. Our goal was to evaluate the protein expression profiles via a global proteomic screening of HGSOC from FFPE samples of both ovaries, with the presumption that one side represents the primary tumor and the other side a metastatic site, eliminating heterogeneity among different tissue types. Following identification, selected proteins involved with migration, cell adhesion, and metastasis were investigated using IHC to assess the correlation of findings
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