The cervical cancer 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 cancer proteome using TCGA transcriptomics data and antibody-based protein data. 732 genes are suggested as prognostic based on transcriptomics data from 291 patients; 223 genes are associated with unfavorable prognosis and 509 genes are associated with favorable 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.

Unfavorable prognostic genes in cervical cancer

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

PON2 is a gene associated with unfavorable 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 a differential expression pattern in cervical cancer samples.

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

LPCAT1 is another gene associated with an unfavorable 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 a differential expression pattern in cervical cancer samples.

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

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

Favorable prognostic genes in cervical cancer

For favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 509 genes associated with a favorable prognosis in cervical cancer. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed.

MCM5 is a gene associated with a favorable 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 a differential expression pattern in cervical cancer samples.

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

ARHGAP4 is another gene associated with a favorable 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 a differential expression pattern in cervical cancer samples.

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

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

The cervical cancer transcriptome

The transcriptome analysis shows that 71% (n=14278) of all human genes (n=20090) 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.

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.

162 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.

Table 3. The number of genes in the subdivided categories of elevated expression 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 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