The cervical cancer proteome


Cervical cancer is the third most common type of cancer in women worldwide. Survival rate varies greatly depending on surgical 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 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 cancer proteome using TCGA transcriptomics data and antibody based protein data. 723 genes are suggested as prognostic based on transcriptomics data from 291 patients; 223 genes associated with unfavourable prognosis and 500 genes associated with favourable prognosis.

TCGA data analysis


In this metadata study we used data from TCGA where transcriptomics data was available from 291 patients in total, with squamous cell carcinoma or adenocarcinoma. Most of the patients (220 patients) were still alive at the time of data collection. Information on stage distribution was missing.

Unfavourable prognostic genes in cervical cancer


For unfavourable genes, higher relative expression levels at diagnosis gives significantly lower overall survival for the patients. There are 223 genes associated with unfavourable prognosis in cervical cancer. In Table 1, the top 20 most significant genes related to unfavourable prognosis are listed.

PON2 is a gene associated with unfavourable prognosis in cervical cancer. The best separation is achieved by an expression cutoff at 16.7 fpkm which divides the patients into two groups with 36 % 5-year survival for patients with high expression versus 77 % for patients with low expression, p-value: 1.43e-5 . Immunohistochemical staining using an antibody targeting PON2 (HPA029193) shows differential expression pattern in cervical cancer samples.

PON2 - survival analysis p<0.001
PON2 - high expression
PON2 - low expression

LPCAT1 is another gene associated with unfavourable prognosis in cervical cancer. The best separation is achieved by an expression cutoff at 16.4 fpkm which divides the patients into two groups with 43 % 5-year survival for patients with high expression versus 72 % for patients with low expression, p-value: 7.11e-5. Immunohistochemical staining using an antibody targeting LPCAT1 (HPA012501) shows differential expression pattern in cervical cancer samples.

LPCAT1 - survival analysis p<0.001
LPCAT1 - high expression
LPCAT1 - low expression

Table 1. The 20 genes with highest significance associated with unfavourable prognosis in cervical cancer.

Gene

Description

Predicted localization

mRNA (cancer)

p-value

EREG epiregulin Membrane 1.1 1.67e-7
ESM1 endothelial cell-specific molecule 1 Secreted 3.3 2.11e-7
EGLN1 egl-9 family hypoxia-inducible factor 1 Intracellular 8.2 2.99e-7
GALNT2 polypeptide N-acetylgalactosaminyltransferase 2 Secreted 23.0 1.22e-6
FUT11 fucosyltransferase 11 (alpha (1,3) fucosyltransferase) Secreted 4.0 2.39e-6
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Favourable prognostic genes in cervical cancer


For favourable genes, higher relative expression levels at diagnosis gives significantly higher overall survival for the patients. There are 500 genes associated with favourable prognosis in cervical cancer. In Table 2, the top 20 most significant genes related to favourable prognosis are listed.

MCM5 is a gene associated with favourable prognosis in cervical cancer. The best separation is achieved by an expression cutoff at 21.2 fpkm which divides the patients into two groups with 72 % 5-year survival for patients with high expression versus 34 % for patients with low expression, p-value: 2.81e-6. Immunohistochemical staining using an antibody targeting MCM5 (CAB000101) shows differential expression pattern in cervical cancer samples.

MCM5 - survival analysis p<0.001
MCM5 - high expression
MCM5 - low expression

ARHGAP4 is another gene associated with favourable prognosis in cervical cancer. The best separation is achieved by an expression cutoff at 17.0 fpkm which divides the patients into two groups with 79 % 5-year survival for patients with high expression versus 53 % for patients with low expression, p-value: 3.94e-5. Immunohistochemical staining using an antibody targeting ARHGAP4 (HPA001012) shows differential expression pattern in cervical cancer samples.

ARHGAP4 - survival analysis p<0.001
ARHGAP4 - high expression
ARHGAP4 - low expression

Table 2. The 20 genes with highest significance associated with favourable prognosis in cervical cancer.

Gene

Description

Predicted localization

mRNA (cancer)

p-value

EAF2 ELL associated factor 2 Intracellular 4.0 2.25e-9
SSBP3 single stranded DNA binding protein 3 Intracellular 21.3 2.48e-9
NCAPH2 non-SMC condensin II complex, subunit H2 Intracellular 31.4 2.24e-8
KIF22 kinesin family member 22 Intracellular 28.5 3.87e-8
RIBC2 RIB43A domain with coiled-coils 2 Intracellular 8.7 7.08e-8
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The cervical cancer transcriptome


The transcriptome analysis shows that 71% (n=13806) of all human genes (n=19571) are expressed in cervical cancer. All genes were classified according to the cervical cancer-specific expression into one of five different categories, based on the ratio between mRNA levels in cervical cancer compared to the mRNA levels in the other 16 analyzed cancer tissues. 112 genes show some level of elevated expression in cervical cancer compared to other cancers (Figure 1). The elevated category is further subdivided into three categories as shown in Table 3.

Figure 1. The distribution of all genes across the five categories based on transcript abundance in cervical cancer as well as in all other cancer tissues.

Table 3. Number of genes in the subdivided categories of elevated expression in cervical cancer

Category

Number of genes

Description

Tissue enriched 1 At least five-fold higher mRNA levels in a particular cancer as compared to all other cancers
Group enriched 74 At least five-fold higher mRNA levels in a group of 2-7 cancers
Tissue enhanced 37 At least five-fold higher mRNA levels in a particular cancer as compared to average levels in all cancers
Total 112 Total number of elevated genes in cervical cancer

Additional information


Cervical cancers arise from cells in the transitional zone of the cervix. The transitional zone is the border between squamous epithelium, that cover the distal portion of 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 which 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, 2017. A pathology atlas of the human cancer transcriptome. Science.
PubMed: 28818916 DOI: 10.1126/science.aan2507

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

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

Histology dictionary - Cervical cancer