The endometrial cancer proteome

Endometrial cancer is the fifth most common cancer in women, and one of the most common forms of gynecological cancer in developed countries. The incidence of endometrial cancer is rising and this is believed to be related to increased life expectancy and the epidemic of obesity. The 5-year survival rate in patients without metastatic disease varies from 74% to 91%. Around 80% of endometrial cancers represent endometrioid histology. These are considered hormone dependent and the prognosis of endometrioid cancers is generally favorable. The majority of endometrial cancers are detected at an early stage with the disease restricted to the uterus.

Endometrial cancer originates from the endometrium - the mucosal lining of the uterus. The common form of endometrial cancer, referred to as type 1 or estrogen-related endometrial cancer, usually occurs in younger, premenopausal women and tends to be of lower histologic grade. Type 2, or non-estrogen-related endometrial cancer, occurs in postmenopausal women, and is the more aggressive form of endometrial cancer.

Here, we explore the endometrial cancer proteome using TCGA transcriptomics data and antibody-based protein data. 1635 genes are suggested as prognostic based on transcriptomics data from 541 patients; 787 genes are associated with unfavorable prognosis and 848 genes are associated with favorable prognosis.

TCGA data analysis

In this metadata study, we used data from TCGA where transcriptomics data was available from 541 patients in total and dataset included only females . Most of the patients (450 patients) were still alive at the time of data collection. All patients (541) were missing stage information.

Unfavorable prognostic genes in endometrial cancer

For unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 787 genes associated with an unfavorable prognosis in endometrial cancer. In Table 1, the top 20 most significant genes related to an unfavorable prognosis are listed.

ASS1 is a gene associated with an unfavorable prognosis in endometrial cancer. The best separation is achieved by an expression cutoff at 45,2 fpkm which divides the patients into two groups with 63% 5-year survival for patients with high expression versus 86% for patients with low expression, p-value: 8,14e-9. Immunohistochemical staining of an antibody targeting ASS1 (HPA020896) shows variable staining intensities in endometrial cancer samples.

p<0.001
ASS1 - survival analysis
ASS1 - high expression
ASS1 - low expression

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

Gene	Description	Predicted location	mRNA (cancer)	p-value
L1CAM	L1 cell adhesion molecule	Intracellular,Membrane	6.2	8.51e-10
MBOAT2	membrane bound O-acyltransferase domain containing 2	Membrane	2.9	2.13e-9
HIF3A	hypoxia inducible factor 3 subunit alpha	Intracellular	1.4	6.90e-9
ASS1	argininosuccinate synthase 1	Intracellular	59.5	8.14e-9
PTX3	pentraxin 3	Secreted	1.3	8.35e-9
FAM110B	family with sequence similarity 110 member B	Intracellular	1.9	3.88e-8
IGSF1	immunoglobulin superfamily member 1	Intracellular,Membrane	1.1	4.25e-8
MGAT4A	alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A	Intracellular,Secreted	3.8	6.48e-8
KHK	ketohexokinase	Intracellular	1.3	7.62e-8
MARK4	microtubule affinity regulating kinase 4	Intracellular,Membrane	7.9	8.31e-8
GPRIN2	G protein regulated inducer of neurite outgrowth 2	Intracellular	1.2	8.60e-8
ERBB2	erb-b2 receptor tyrosine kinase 2	Intracellular,Membrane	43.3	8.99e-8
LMO3	LIM domain only 3	Intracellular	1.3	1.10e-7
DAGLA	diacylglycerol lipase alpha	Membrane	1.2	1.13e-7
ADA	adenosine deaminase	Intracellular	4.3	1.23e-7
MAP1LC3C	microtubule associated protein 1 light chain 3 gamma	Intracellular	1.2	1.34e-7
CDKN2A	cyclin dependent kinase inhibitor 2A	Intracellular	14.3	1.82e-7
RNF44	ring finger protein 44	Intracellular	12.6	2.57e-7
LRRN2	leucine rich repeat neuronal 2	Membrane	10.6	2.59e-7
TRIM46	tripartite motif containing 46	Intracellular	1.5	2.61e-7
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Favorable prognostic genes in endometrial cancer

For favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 848 genes associated with a favorable prognosis in endometrial cancer. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed.

SCGB2A1 is a gene associated with a favorable prognosis in endometrial cancer. The best separation is achieved by an expression cutoff at 36.7 fpkm which divides the patients into two groups with 82% 5-year survival for patients with high expression versus 56% for patient with low expression, p-value: 1,54e-8. Immunohistochemical staining of antibody targeting SCGB2A1 (HPA034584) shows variable staining in endometrial cancer samples.

p<0.001
SCGB2A1 - survival analysis
SCGB2A1 - high expression
SCGB2A1 - low expression

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

Gene	Description	Predicted location	mRNA (cancer)	p-value
B4GALNT3	beta-1,4-N-acetyl-galactosaminyltransferase 3	Intracellular	20.8	1.69e-10
P2RX4	purinergic receptor P2X 4	Membrane	7.4	6.30e-10
SPDEF	SAM pointed domain containing ETS transcription factor	Intracellular	78.1	9.26e-9
SCGB2A1	secretoglobin family 2A member 1	Secreted	971.9	1.54e-8
DHRS7B	dehydrogenase/reductase 7B	Intracellular,Membrane	8.6	1.98e-8
PLPP2	phospholipid phosphatase 2	Membrane	28.2	3.21e-8
TRBC2	T cell receptor beta constant 2	Membrane	14.2	3.42e-8
NXNL2	nucleoredoxin like 2	Intracellular	4.0	3.83e-8
SMDT1	single-pass membrane protein with aspartate rich tail 1	Membrane	31.4	5.32e-8
SLC47A1	solute carrier family 47 member 1	Membrane	14.6	5.54e-8
HEXA	hexosaminidase subunit alpha	Intracellular	6.8	5.63e-8
PGR	progesterone receptor	Intracellular	11.1	5.76e-8
STX18	syntaxin 18	Intracellular,Membrane	43.1	6.33e-8
ATP5IF1	ATP synthase inhibitory factor subunit 1	Intracellular	76.6	6.38e-8
DRAM1	DNA damage regulated autophagy modulator 1	Intracellular,Membrane	7.7	6.52e-8
SPAG4	sperm associated antigen 4	Intracellular,Membrane	8.7	9.52e-8
SCGB2A2	secretoglobin family 2A member 2	Secreted	35.9	9.57e-8
ZAP70	zeta chain of T cell receptor associated protein kinase 70	Intracellular	1.9	9.66e-8
GPR108	G protein-coupled receptor 108	Intracellular,Membrane	21.7	1.04e-7
MSX1	msh homeobox 1	Intracellular	246.3	1.64e-7
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The endometrial cancer transcriptome

The transcriptome analysis shows that 73% (n=14572) of all human genes (n=20090) are expressed in endometrial cancer. All genes were classified according to the endometrial cancer-specific expression into one of five different categories, based on the ratio between mRNA levels in endometrial 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 endometrial cancer as well as in all other cancer tissues.

260 genes show some level of elevated expression in endometrial 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 endometrial cancer.

		Distribution in the 17 cancers
		Detected in single	Detected in some	Detected in many	Detected in all	Total
Specificity	Cancer enriched	11	6	11	3	31
	Group enriched	0	45	39	12	96
	Cancer enhanced	25	43	60	5	133
	Total	36	94	110	20	260

Additional information

High estrogen blood levels stimulate the endometrial mucosa, which may result in excessive endometrial growth and type 1 endometrial cancer. Conditions such as diabetes, infertility, obesity, and polycystic ovarian syndrome (PCOS) are associated with an increased risk to develop type 1 endometrial carcinoma. Infrequent periods, first menstruation before the age of 12, no pregnancies, and entering menopause after the age of 50 is also associated with an increased risk, as is receiving estrogen replacement therapy (without progesterone) or tamoxifen treatment, a common drug for the treatment of breast cancer. Factors that predispose for type 2 endometrial cancer are less well-known.

Certain correlations exist between the type of endometrial cancer and histology. Type 1 cancers are usually low-grade, have an endometrioid appearance and are associated with hyperplasia in the adjacent endometrium. Type 2 usually consists of high-grade, serous or clear cell tumors and is not associated with endometrial hyperplasia.

Endometrial cancers are popularly staged according to the FIGO (International Federation of Gynaecology and Obstetrics) staging system. Stage I cancers are limited to the uterine corpus (or body). Stage II tumors involve the cervix, while Stage III tumors involve the serosa and/or uterine adnexa, vagina, and pelvic lymph nodes. In Stage IV distant metastases are present.

Histologic grade in endometrial cancers is defined on the basis of tubular differentiation and nuclear pleomorphism. Well-differentiated (Grade 1) endometrial cancers show uniform oval nuclei with evenly dispersed chromatin and a solid tumor growth pattern (without lumen formation) only in a small fraction of the tumor. In poorly differentiated cancers (Grade 3) nuclei with coarse chromatin and prominent nucleoli are observed and more than 50% of the tumor is composed of solid masses.

Immunohistochemistry for estrogen alpha (ER, ESR1) and progesterone receptors (PR, PGR) shows that these hormonal receptors are typically expressed in tumor cells in type 1, but frequently not in type 2 endometrial 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

Zieba A et al., The Human Endometrium-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling. OMICS. (2015)
PubMed: 26488136 DOI: 10.1089/omi.2015.0115

Histology dictionary - Endometrial cancer