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The ovary serous cystadenocarcinoma proteomeEpithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women. 50% of all ovarian cancers are diagnosed in women older than 65 years of age. Approximately 5 to 10% of ovarian cancers are familial and women with mutations in the genes BRCA1 or BRCA2 have about a 50% higher risk of developing ovarian cancer. Ovarian cancer is typically denoted as a silent cancer since symptoms occur late in the course of the disease. A majority of ovarian epithelial cancers are diagnosed during or after abdominal exploration to investigate a pelvic or abdominal mass detected on physical examination. By the time of discovery, approximately 70% of the tumors have spread beyond the ovary and are in such cases rarely curable by surgical resection or surgery combined with postoperative chemotherapy and/or radiation therapy. The dismal prognosis has stimulated research efforts for early detection of ovarian cancer. Ovarian epithelial cancer is bilateral (involving both ovaries) in one-third to one-half of the cases. The FIGO (International Federation of Gynaecology and Obstetrics) staging system recognizes four stages for ovarian cancer. Patients with Stage I tumors have a 5-year survival of 80%, while the 5-year survival of Stage IV patients is merely 8%. Here, we explore the ovary serous cystadenocarcinoma proteome using TCGA transcriptomics data and antibody-based protein data. 901 genes are suggested as prognostic based on transcriptomics data from 349 patients; 715 genes are associated with unfavorable prognosis and 186 genes are associated with favorable prognosis. TCGA data analysisIn this metadata study, we used data from TCGA where transcriptomics data was available from 349 females with ovarian serous cystadenocarcinoma. A minority of the patients (132 patients) were still alive at the time of data collection. The stage distribution was stage i) 1 patient, stage ii) 19 patients, stage iii) 271 patients, stage iv) 55 patients, and 3 patients with missing stage information. Unfavorable prognostic genes in ovary serous cystadenocarcinomaFor unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 715 genes associated with an unfavorable prognosis in ovary serous cystadenocarcinoma, among these potential prognostic genes there are 17 genes that were validated in a separate study. In Table 1, the top 20 most significant genes related to an unfavorable prognosis are listed. KRT7 is a gene associated with unfavorable prognosis in ovary serous cystadenocarcinoma. The best separation is achieved by an expression cutoff at 480 TPM which divides the patients into two groups with 17% 5-year survival for patients with high expression versus 38% for patients with low expression, p-value: 9.18e-5. The Keratin type II cytoskeletal 7, or KRT7, is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are co-expressed during differentiation of simple and stratified epithelial tissues. KRT7 is involved in the translational regulation of the human papillomavirus type 16 E7 mRNA (HPV16 E7). Immunohistochemical staining using an antibody targeting KRT7 (CAB000028) shows a differential expression pattern in ovary serous cystadenocarcinoma samples.
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MRC2 is another gene associated with unfavorable prognosis in ovary serous cystadenocarcinoma. The best separation is achieved by an expression cutoff at 29 TPM which divides the patients into two groups with 19% 5-year survival for patients with high expression versus 34% for patients with low expression, p-value: 7.83e-4. C-type mannose receptor 2 is encoded by this gene and plays a role in extracellular matrix remodeling by mediating the internalization and lysosomal degradation of collagen ligands. The expression of MRC2 may play a role in the tumorigenesis and metastasis of several malignancies. Immunohistochemical staining using an antibody targeting MRC2 (HPA041991) shows a differential expression pattern in ovary serous cystadenocarcinoma samples.
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Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in ovary serous cystadenocarcinoma.
Favorable prognostic genes in ovary serous cystadenocarcinomaFor favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 186 genes associated with a favorable prognosis in ovary serous cystadenocarcinoma. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed. NOL7 is a gene associated with favorable prognosis in ovary serous cystadenocarcinoma. The best separation is achieved by an expression cutoff at 36 TPM which divides the patients into two groups with 41% 5-year survival for patients with high expression versus 19% for patients with low expression, p-value: 1.47e-5. Nucleolar protein 7 is encoded by this gene and localizes to the nucleolus, where it maintains nucleolar structure and cell growth rates. NOL7 also functions as a tumor suppressor and regulator of angiogenesis. The RB tumor suppressor gene recruits transcription factors to NOL7 and positively regulates its expression. Immunohistochemical staining using an antibody targeting NOL7 (HPA029185) shows a differential expression pattern in ovary serous cystadenocarcinoma samples.
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Table 2. The 20 genes with highest significance associated with a favorable prognosis in ovary serous cystadenocarcinoma.
CPTAC relative protein expression dataProteins that are significantly down- or upregulated in ovary serous cystadenocarcinoma compared to normal tissue is illustrated in a vulcano plot using tandem mass tag (TMT) mass spectrometry data from the CPTAC dataset based on the analysis of 85 tumor samples and 23 normal samples. In ovary serous cystadenocarcinoma, 461 and 625 genes are down- (blue) and upregulated (red) compared to normal tissue, respectively. In Table 3, the top 20 most significant genes are listed.
Table 3. The 20 genes with the highest significance associated with a downregulated or upregulated protein expression in ovary serous cystadenocarcinoma compared to normal tissue.
The ovary serous cystadenocarcinoma transcriptomeThe transcriptome analysis shows that 69% (n=13852) of all human genes (n=20162) are expressed in ovary serous cystadenocarcinoma. All genes were classified according to the ovary serous cystadenocarcinoma-specific expression into one of five different categories, based on the ratio between mRNA levels in ovary serous cystadenocarcinoma compared to the mRNA levels in the other 16 analyzed cancer tissues.
Figure 2. The distribution of all genes across the five categories based on transcript abundance in ovary serous cystadenocarcinoma as well as in all other cancer tissues. 211 genes show some level of elevated expression in ovary serous cystadenocarcinoma compared to other cancers (Figure 1). The elevated category is further subdivided into three categories as shown in Table 3. Table 4. The number of genes in the subdivided categories of elevated expression in ovary serous cystadenocarcinoma.
Additional informationOvarian epithelial cancers are classified into serous, mucinous, endometrioid, clear cell, transitional cell, squamous cell, mixed epithelial and undifferentiated categories depending on histomorphologic features. The most common forms include sero-papillary, mucinous and endometrioid subtypes. Several histologic grading systems have been proposed with the WHO system being widely employed. Grade 1 (well-differentiated) endometrial cancers show less than 5% of solid tumor growth pattern (without lumen formation) and uniform oval nuclei with evenly dispersed chromatin. In Grade 3 (poorly differentiated) cancers more than 50% of the tumor is composed of solid tumor cell masses and tumor cell nuclei show coarse chromatin and prominent nucleoli. In Grade 2 cancers, between 6-50% of the tumor is composed of solid masses and nuclei display intermediate features compared to Grade 1 and Grade 3 cancers. Relevant links and publications Uhlen M et al., A pathology atlas of the human cancer transcriptome. Science. (2017) |
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