The current WHO classification does not separate transitional cell-like carcinoma of the ovary (TCC) from conventional tubo-ovarian high-grade serous carcinoma (HGSC), despite evidence suggesting improved prognosis for patients with TCC; it is considered, instead a morphologic variant of HGSC. The immunohistochemical (IHC) markers applied to date do not distinguish between TCC and HGSC. Therefore, we sought to compare the proteomic profiles of TCC and conventional HGSC to identify proteins enriched in TCC. Prognostic biomarkers in HGSC have proven elusive and our aim was to identify biomarkers of TCC as a way of reliably and reproducibly identifying patients with a favorable prognosis and better response to chemotherapy compared to those with conventional HGSC. Quantitative global proteome analysis was performed on archival material of 12 cases of TCC and 16 cases of HGSC using SP3-CTP, a recently described protocol for full proteome analysis from formalin-fixed paraffin-embedded tissues. We identified 430 proteins that were significantly enriched in TCC over HGSC. Unsupervised co-clustering perfectly separated TCC from HGSC based on protein expression. Pathway analysis showed that proteins associated with cell death, necrosis and apoptosis were highly expressed in TCCs, while DNA homologous recombination, cell mitosis, proliferation and survival and cell cycle progression pathways had reduced expression. From the proteomic analysis, three potential biomarkers for TCC were identified, claudin-4 (CLDN4), ubiquitin carboxyl-terminal esterase L1 (UCHL1) and minichromosome maintenance protein 7 (MCM7) and tested by IHC on tissue microarrays. In agreement with the proteomic analysis, IHC expression for those proteins was stronger in TCC compared to HGSC (p<0.0001). Using global proteomic analysis, we are able to separate TCC from conventional HGSC. Follow up studies will be necessary to confirm that these molecular and morphologic differences are clinically significant.
Journal
Human Pathology