The ovarian cancer 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 ovarian cancer proteome using TCGA transcriptomics data and antibody based protein data. 509 genes are suggested as prognostic based on transcriptomics data from 373 patients; 152 genes associated with unfavourable prognosis and 357 genes associated with favourable prognosis. TCGA data analysisIn this metadata study we used data from TCGA where transcriptomics data was available from 373 females with ovarian serous cystadenocarcinoma. 143 of the patients were still alive at the time of data collection. Information on stage distribution was missing. Unfavourable prognostic genes in ovarian cancerFor unfavourable genes, higher relative expression levels at diagnosis gives significantly lower overall survival for the patients. There are 152 genes associated with unfavourable prognosis in ovarian cancer. In Table 1, the top 20 most significant genes related to unfavourable prognosis are listed. KRT7 is a gene associated with unfavourable prognosis in ovarian cancer. The best separation is achieved by an expression cutoff at 181.1 fpkm which divides the patients into two groups with 16% 5-year survival for patients with high expression versus 38% for patients with low expression, p-value: 9.42e-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 differential expression pattern in ovarian cancer samples.
p<0.001
MRC2 is another gene associated with unfavourable prognosis in ovarian cancer. The best separation is achieved by an expression cutoff at 23.6 fpkm which divides the patients into two groups with 22% 5-year survival for patients with high expression versus 34% for patients with low expression, p-value: 1.68e-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. Expression of MRC2 may play a role in the tumorigenesis and metastasis of several malignancies. Immunohistochemical staining using an antibody targeting MRC2 (HPA041991) shows differential expression pattern in ovarian cancer samples.
p<0.001
Table 1. The 20 genes with highest significance associated with unfavourable prognosis in ovarian cancer.
Favourable prognostic genes in ovarian cancerFor favourable genes, higher relative expression levels at diagnosis gives significantly higher overall survival for the patients. There are 357 genes associated with favourable prognosis in ovarian cancer. In Table 2, the top 20 most significant genes related to favourable prognosis are listed. NOL7 is a gene associated with favourable prognosis in ovarian cancer. The best separation is achieved by an expression cutoff at 28.6 fpkm 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: 3.64e-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 differential expression pattern in ovarian cancer samples.
p<0.001
TERF2IP is a another gene associated with favourable prognosis in ovarian cancer. The best separation is achieved by an expression cutoff at 12.0 fpkm which divides the patients into two groups with 38% 5-year survival for patients with high expression versus 16% for patients with low expression, p-value: 6.14e-5. Telomeric repeat-binding factor 2-interacting protein 1 is encoded by this gene and plays a role in regulation of transcription and telomere function. When cytoplasmic, TERF2IP associates with the I-kappa-B-kinase (IKK) complex and acts as a regulator of the NF-kappa-B signaling by promoting IKK-mediated phosphorylation of RELA/p65, leading to activate expression of NF-kappa-B target genes. Immunohistochemical staining using an antibody targeting TERF2IP (CAB018660) shows differential expression pattern in ovarian cancer samples.
p<0.001
Table 2. The 20 genes with highest significance associated with favourable prognosis in ovarian cancer.
The ovarian cancer transcriptomeThe transcriptome analysis shows that 72% (n=14227) of all human genes (n=19670) are expressed in ovarian cancer. All genes were classified according to the ovarian cancer-specific expression into one of five different categories, based on the ratio between mRNA levels in ovarian cancer compared to the mRNA levels in the other 16 analyzed cancer tissues.
Figure 1. The distribution of all genes across the five categories based on transcript abundance in ovarian cancer as well as in all other cancer tissues. 151 genes show some level of elevated expression in ovarian cancer compared to other cancers (Figure 1). The elevated category is further subdivided into three categories as shown in Table 3. Table 3. Number of genes in the subdivided categories of elevated expression in ovarian cancer.
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, 2017. A pathology atlas of the human cancer transcriptome. Science. |
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