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.
Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in endometrial cancer.
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.
Table 2. The 20 genes with highest significance associated with a favorable prognosis in endometrial cancer.
The endometrial cancer transcriptome
The transcriptome analysis shows that 73% (n=14631) of all human genes (n=20162) 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.
259 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.
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)