The ovarian cancer proteome

Epithelial 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. 510 genes are suggested as prognostic based on transcriptomics data from 373 patients; 152 genes are associated with unfavorable prognosis and 358 genes are associated with favorable prognosis.

TCGA data analysis

In 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.

Unfavorable prognostic genes in ovarian cancer

For unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 152 genes associated with an unfavorable prognosis in ovarian cancer. 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 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 a differential expression pattern in ovarian cancer samples.

p<0.001
KRT7 - survival analysis
KRT7 - high expression
KRT7 - low expression

MRC2 is another gene associated with an unfavorable 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. 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 ovarian cancer samples.

p<0.001
MRC2 - survival analysis
MRC2 - high expression
MRC2 - low expression

Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in ovarian cancer.

Gene	Description	Predicted location	mRNA (cancer)	p-value
EMP1	epithelial membrane protein 1	Intracellular,Membrane	15.0	2.26e-8
PI3	peptidase inhibitor 3	Secreted	73.6	3.84e-6
FAM20C	FAM20C golgi associated secretory pathway kinase	Secreted	14.0	9.40e-6
FCGBP	Fc fragment of IgG binding protein	Intracellular,Secreted	5.1	9.70e-6
TGFBI	transforming growth factor beta induced	Intracellular,Secreted	21.9	1.14e-5
RCBTB1	RCC1 and BTB domain containing protein 1	Intracellular	5.2	1.21e-5
PPTC7	protein phosphatase targeting COQ7	Intracellular	4.4	1.43e-5
TIMP3	TIMP metallopeptidase inhibitor 3	Secreted	3.3	1.90e-5
SLC39A13	solute carrier family 39 member 13	Membrane	13.7	2.73e-5
AGFG1	ArfGAP with FG repeats 1	Intracellular	8.1	3.43e-5
RPL7A	ribosomal protein L7a	Intracellular	522.3	3.60e-5
UNC5B	unc-5 netrin receptor B	Membrane	13.1	3.80e-5
CST4	cystatin S	Secreted	1.3	4.98e-5
FANCD2	FA complementation group D2	Intracellular	2.8	5.00e-5
RIPK4	receptor interacting serine/threonine kinase 4	Intracellular	7.8	6.22e-5
DAGLB	diacylglycerol lipase beta	Membrane	4.1	7.18e-5
PC	pyruvate carboxylase	Intracellular	3.3	7.86e-5
SOGA1	suppressor of glucose, autophagy associated 1	Intracellular,Secreted	11.8	8.28e-5
FAM98C	family with sequence similarity 98 member C	Intracellular	5.0	8.51e-5
RPS6KA2	ribosomal protein S6 kinase A2	Intracellular	4.9	8.63e-5
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Favorable prognostic genes in ovarian cancer

For favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 358 genes associated with a favorable prognosis in ovarian cancer. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed.

NOL7 is a gene associated with a favorable 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 a differential expression pattern in ovarian cancer samples.

p<0.001
NOL7 - survival analysis
NOL7 - high expression
NOL7 - low expression

TERF2IP is another gene associated with a favorable 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 the 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 a differential expression pattern in ovarian cancer samples.

p<0.001
TERF2IP - survival analysis
TERF2IP - high expression
TERF2IP - low expression

Table 2. The 20 genes with highest significance associated with a favorable prognosis in ovarian cancer.

Gene	Description	Predicted location	mRNA (cancer)	p-value
MRS2	magnesium transporter MRS2	Membrane	9.2	5.14e-11
ZNF429	zinc finger protein 429	Intracellular	2.7	1.96e-8
TDP2	tyrosyl-DNA phosphodiesterase 2	Intracellular	12.9	2.53e-7
CXCL11	C-X-C motif chemokine ligand 11	Secreted	8.7	4.31e-7
GPR27	G protein-coupled receptor 27	Membrane	11.5	1.21e-6
MED19	mediator complex subunit 19	Intracellular	13.2	1.76e-6
C18orf21	chromosome 18 open reading frame 21	Intracellular	6.8	1.81e-6
ACOT13	acyl-CoA thioesterase 13	Intracellular	5.3	2.53e-6
UBE2L3	ubiquitin conjugating enzyme E2 L3	Intracellular	28.8	3.82e-6
KLHDC9	kelch domain containing 9	Intracellular	9.4	4.20e-6
AP1S2	adaptor related protein complex 1 subunit sigma 2	Intracellular	6.4	5.53e-6
MAGOHB	mago homolog B, exon junction complex subunit	Intracellular	5.0	5.56e-6
AADAC	arylacetamide deacetylase	Intracellular	2.8	5.58e-6
FMC1	formation of mitochondrial complex V assembly factor 1 homolog	Intracellular	9.2	5.63e-6
FAM166B	family with sequence similarity 166 member B	Intracellular	4.3	6.20e-6
ZNF85	zinc finger protein 85	Intracellular	1.9	6.45e-6
PRR3	proline rich 3	Intracellular	6.5	6.49e-6
UBE2T	ubiquitin conjugating enzyme E2 T	Intracellular	28.9	6.90e-6
CCDC160	coiled-coil domain containing 160	Intracellular	1.6	7.62e-6
SNRPD1	small nuclear ribonucleoprotein D1 polypeptide	Intracellular	12.3	7.90e-6
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The ovarian cancer transcriptome

The transcriptome analysis shows that 72% (n=14467) of all human genes (n=20090) 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.

218 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. The number of genes in the subdivided categories of elevated expression in ovarian cancer.

		Distribution in the 17 cancers
		Detected in single	Detected in some	Detected in many	Detected in all	Total
Specificity	Cancer enriched	4	6	6	1	17
	Group enriched	0	36	38	10	84
	Cancer enhanced	14	33	55	15	117
	Total	18	75	99	26	218

Additional information

Ovarian 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)
PubMed: 28818916 DOI: 10.1126/science.aan2507

Cancer Genome Atlas Research Network et al., The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. (2013)
PubMed: 24071849 DOI: 10.1038/ng.2764

Uhlén M et al., Tissue-based map of the human proteome. Science (2015)
PubMed: 25613900 DOI: 10.1126/science.1260419

Histology dictionary - Ovarian cancer