Abstract
Ovarian carcinomas are a group of distinct diseases classified by histotypes. As histotype-specific treatment evolves, accurate classification will become critical for optimal precision medicine approaches. To uncover differences between the two most common histotypes, high-grade serous (HGSC) and endometrioid carcinoma, we performed label-free quantitative proteomics on freshly frozen tumor tissues (HGSC, n = 10; endometrioid carcinoma, n = 10). Eight candidate protein biomarkers specific to endometrioid carcinoma were validated by IHC using tissue microarrays representing 361 cases of either endometrioid carcinoma or HGSC. More than 500 proteins were differentially expressed (P < 0.05) between endometrioid carcinoma and HGSC tumor proteomes. A ranked set of 106 proteins was sufficient to correctly discriminate 90% of samples. IHC validated KIAA1324 as the most discriminatory novel biomarker for endometrioid carcinoma. An 8-marker panel was found to exhibit superior performance for discriminating endometrioid carcinoma from HGSC compared with the current standard of WT1 plus TP53 alone, improving the classification rate for HGSC from 90.7% to 99.2%. Endometrioid carcinoma-specific diagnostic markers such as PLCB1, KIAA1324, and SCGB2A1 were also significantly associated with favorable prognosis within endometrioid carcinoma suggesting biological heterogeneity within this histotype. Pathway analysis of proteomic data revealed differences between endometrioid carcinoma and HGSC pertaining to estrogen and interferon signalling. In summary, these findings support the use of multi-marker panels for the differential diagnosis of difficult cases resembling endometrioid carcinoma and HGSC.
Highlights
Ovarian cancer affects 1.27% of females in the United States and remains a difficult disease to treat with an overall 5-year survival of only 46% [1]
An 8-marker panel was found to exhibit superior performance for discriminating endometrioid carcinoma from HGSC compared with the current standard of WT1 plus TP53 alone, improving the classification rate for HGSC from 90.7% to 99.2%
Endometrioid carcinoma–specific diagnostic markers such as PLCB1, KIAA1324, and SCGB2A1 were significantly associated with favorable prognosis within endometrioid carcinoma suggesting biological heterogeneity within this histotype
Summary
Ovarian cancer affects 1.27% of females in the United States and remains a difficult disease to treat with an overall 5-year survival of only 46% [1]. Classified into five major histotypes, which are in descending order of frequency: high-grade serous (HGSC), endometrioid, clear cell (CCC), low-grade serous, and mucinous carcinoma [2]. These histotypes differ with respect to their underlying molecular alterations and outcomes. Hormonal therapy is a treatment option for low-stage endometrioid carcinoma and immunotherapy is emerging as an option for metastatic endometrioid carcinoma that are associated with defects in DNA mismatch repair genes [7,8,9,10]. HGSC should be tested for BRCA1/2 germline mutations and endometrioid carcinoma for mismatch repair deficiency and underlying Lynch syndrome
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