The cervical squamous cell carcinoma and endocervical adenocarcinoma proteome

Cervical cancer is the third most common type of cancer in women worldwide. The survival rate varies greatly depending on the cancer stage. With treatment, 80 to 90% of women with stage I and 50 to 65% with stage II cancer are alive 5-years after diagnosis. Only 25 to 35% of women with stage III cancer and 15% or fewer of those with stage IV cancer are alive after 5 years.

Two strains of Human Papilloma Virus (HPV), that can spread through sexual intercourse, are the cause of nearly all cervical cancers. Risk factors include having sex at an early age, multiple sexual partners, smoking and poor socio-economic status. There is an approved vaccine for the prevention of HPV infection.

Most cervical cancers are squamous cell carcinomas originating from the squamous epithelium of the distal portion of the cervix. Cancers arising from the columnar cells in the endocervical channel are defined as adenocarcinomas and are more rare.

Here, we explore the cervical squamous cell carcinoma and endocervical adenocarcinoma proteome using TCGA transcriptomics data and antibody-based protein data. 822 genes are suggested as prognostic based on transcriptomics data from 283 patients; 423 genes are associated with unfavorable prognosis and 399 genes are associated with favorable prognosis.

TCGA data analysis

In this metadata study, we used data from TCGA where transcriptomics data was available from 283 patients in total, with squamous cell carcinoma or adenocarcinoma. Most of the patients (215 patients) were still alive at the time of data collection. The stage distribution was stage i) 154 patients, stage ii) 63 patients, stage iii) 39 patients, stage iv) 21 patients, and 6 patients with missing stage information.

Unfavorable prognostic genes in cervical squamous cell carcinoma and endocervical adenocarcinoma

For unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 423 genes associated with an unfavorable prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma. In Table 1, the top 20 most significant genes related to an unfavorable prognosis are listed.

PDK1 is a gene associated with unfavorable prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma. The best separation is achieved by an expression cutoff at 10 TPM which divides the patients into two groups with 37% 5-year survival for patients with high expression versus 71% for patients with low expression, p-value: 2.89e-7 . Immunohistochemical staining using an antibody targeting PDK1 (HPA027376) shows a differential expression pattern in cervical squamous cell carcinoma samples.

p<0.001 0.00.10.20.30.40.50.60.70.80.91.0 0 1 2 3 4 5 6 7 8 91011121314151617
PDK1 - survival analysis

PDK1 - high expression

PDK1 - low expression

Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma.

Gene
Description
Predicted location
mRNA (cancer)
p-value
Prognostic
PMEPA1 Prostate transmembrane protein, androgen induced 1 Membrane, Intracellular 50.9 1.22e-6 potential
PTPRB Protein tyrosine phosphatase receptor type B Membrane, Intracellular 2.3 9.01e-6 potential
CXCL2 C-X-C motif chemokine ligand 2 Secreted 15.4 2.23e-5 potential
CFL1 Cofilin 1 Intracellular 1091.3 4.83e-5 potential
TMOD3 Tropomodulin 3 Intracellular 20.7 5.85e-5 potential
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Favorable prognostic genes in cervical squamous cell carcinoma and endocervical adenocarcinoma

For favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 399 genes associated with a favorable prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed.

MRPS11 is a gene associated with a favorable prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma. The best separation is achieved by an expression cutoff at 8.5 TPM which divides the patients into two groups with 72% 5-year survival for patients with high expression versus 40% for patients with low expression, p-value: 1.35e-6. Immunohistochemical staining using an antibody targeting MRPS11 (HPA043752) shows a differential expression pattern in cervical squamous cell carcinoma samples.

p<0.001 0.00.10.20.30.40.50.60.70.80.91.0 0 1 2 3 4 5 6 7 8 91011121314151617
MRPS11 - survival analysis

MRPS11 - high expression

MRPS11 - low expression

Table 2. The 20 genes with highest significance associated with a favorable prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma.

Gene
Description
Predicted location
mRNA (cancer)
p-value
Prognostic
SLC2A8 Solute carrier family 2 member 8 Membrane 15.1 1.00e-5 potential
CLEC3B C-type lectin domain family 3 member B Secreted, Intracellular 4.5 1.99e-5 potential
SLC25A38 Solute carrier family 25 member 38 Membrane, Intracellular 16.9 3.46e-5 potential
RPA3 Replication protein A3 Intracellular 56.2 5.77e-5 potential
LSM7 LSM7 homolog, U6 small nuclear RNA and mRNA degradation associated Intracellular 166.1 7.16e-5 potential
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The cervical squamous cell carcinoma and endocervical adenocarcinoma transcriptome

The transcriptome analysis shows that 71% (n=14269) of all human genes (n=20162) are expressed in cervical squamous cell carcinoma and endocervical adenocarcinoma. All genes were classified according to the cervical squamous cell carcinoma and endocervical adenocarcinoma-specific expression into one of five different categories, based on the ratio between mRNA levels in cervical squamous cell carcinoma and endocervical adenocarcinoma 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 cervical squamous cell carcinoma and endocervical adenocarcinoma as well as in all other cancer tissues.

169 genes show some level of elevated expression in cervical squamous cell carcinoma and endocervical adenocarcinoma 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 cervical squamous cell carcinoma and endocervical adenocarcinoma.

Distribution in the 31 cancers
Detected in singleDetected in someDetected in manyDetected in all Total
Specificity
Cancer enriched 2201 5
Group enriched 019444 67
Cancer enhanced 10284910 97
Total 12499315 169

Additional information

Cervical cancers arise from cells in the transitional zone of the cervix. The transitional zone is the border between squamous epithelium, that covers the distal portion of the cervix (the portio) and the columnar, glandular cells that line the endocervical channel. The FIGO (International Federation of Gynecology and Obstetrics) staging system recognizes four stages of cervical cancer. Stage I depicts cancer limited to the cervix. Stage II denotes cervical cancer that has spread beyond the cervix but not to the lower third of the vagina or the pelvic wall. Stage III cancers have spread to the pelvic wall and/or lower third of the vagina. Stage IV tumors extend beyond the true pelvis or clinically involve the mucosa of the bladder and/or rectum. One of the most common symptoms of cervical cancer is abnormal vaginal bleeding, but in some cases, there may be no obvious symptoms until the cancer is in its advanced stages.

Cervical cancer usually develops very slowly, often over a period of months and years. The initial precancerous form is treatable and can be detected by a Pap smear. Successful cytological screening programs using Pap smear have significantly reduced incidence of cervical cancer.

Most women who are diagnosed with cervical cancer today have not had regular Pap smears or they have not followed up on abnormal Pap smear results. The widespread use of cervical screening programs has reduced the incidence of invasive cervical cancer by 50% or more in countries where such programs successfully have been established. However, Pap smear screening remains a challenge in developing countries such as India and China. Consequently, the incidence of cervical cancer in these countries is high.

In June 2006, the U.S. Food and Drug Administration approved a vaccine that prevents infection by the HPV 16 and 18. Studies have shown that the vaccine appears to prevent precancerous lesions and early-stage cervical cancer.

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 - Cervical cancer