The bladder urothelial carcinoma proteome

Urothelial carcinoma, also termed transitional cell carcinoma or urinary bladder cancer, is a major cause of morbidity and mortality throughout the world. The highest frequency of cancer in the urinary bladder is found among urban Caucasians in Western Europe and in the United States of America. Urothelial cancer typically presents in patients over the age of 50 years and is approximately three times as common in males as in females. Smoking is considered an important risk factor.

Urothelial cancer can be divided into papillary and non-papillary tumors depending on the morphological appearance. Approximately 25% of all urothelial tumors are non-invasive papillary tumors. However, 10-15% of these patients will subsequently develop an invasive tumor.

Here, we explore the bladder urothelial carcinoma proteome using TCGA transcriptomics data and antibody-based protein data. 519 genes are suggested as prognostic based on transcriptomics data from 169 patients; 210 genes are associated with unfavorable prognosis and 309 genes are associated with favorable prognosis.

TCGA data analysis

In this metadata study, we used data from TCGA where transcriptomics data was available from 169 patients in total, where all patients were deceased at the time of sample collection. The dataset included 46 females and 123 males. The stage distribution was stage i) 0 patients, stage ii) 32 patients, stage iii) 55 patients, stage iv) 81 patients and 1 patient with missing stage information.

Unfavorable prognostic genes in bladder urothelial carcinoma

For unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 210 genes associated with an unfavorable prognosis in bladder urothelial carcinoma. In Table 1, the top 20 most significant genes related to an unfavorable prognosis are listed.

PSMD2 is a gene associated with an unfavorable prognosis in bladder urothelial carcinoma. The best separation is achieved by an expression cutoff at 92 TPM which divides the patients into two groups with 1% 5-year survival for patients with high expression versus 8% for patients with low expression, p-value: 6.23e-6. Immunohistochemical staining using an antibody targeting PSMD2 (HPA045192) shows a differential expression pattern in bladder urothelial 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
PSMD2 - survival analysis

PSMD2 - high expression

PSMD2 - low expression

SERBP1 is a gene associated with an unfavorable prognosis in bladder urothelial carcinoma. The best separation is achieved by an expression cutoff at 72 TPM which divides the patients into two groups with 2% 5-year survival for patients with high expression versus 13% for patients with low expression, p-value: 5.78e-5. Immunohistochemical staining using an antibody targeting SERBP1 (CAB026297) shows a differential expression pattern in bladder urothelial 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
SERBP1 - survival analysis

SERBP1 - high expression

SERBP1 - low expression

Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in bladder urothelial carcinoma.

Gene
Description
Predicted location
mRNA (cancer)
p-value
Prognostic
PSMD2 Proteasome 26S subunit ubiquitin receptor, non-ATPase 2 Membrane, Intracellular 110.7 6.23e-6 potential
ENO1 Enolase 1 Intracellular 1229.1 3.82e-5 potential
MRPL36 Mitochondrial ribosomal protein L36 Intracellular 68.9 5.05e-5 potential
SERBP1 SERPINE1 mRNA binding protein 1 Intracellular 136.7 5.78e-5 potential
CCT6A Chaperonin containing TCP1 subunit 6A Intracellular 100.8 1.01e-4 potential
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Favorable prognostic genes in bladder urothelial carcinoma

For favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 309 genes associated with a favorable prognosis in bladder urothelial carcinoma. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed.

FUCA1 is a gene associated with a favorable prognosis in bladder urothelial carcinoma. The best separation is achieved by an expression cutoff at 35 TPM which divides the patients into two groups with 7% 5-year survival for patients with high expression versus 0% for patients with low expression, p-value: 2.90e-5. Immunohistochemical staining using an antibody targeting FUCA1 (HPA046542) shows a differential expression pattern in bladder urothelial 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
FUCA1 - survival analysis

FUCA1 - high expression

FUCA1 - low expression

MYO6 is a gene associated with a favorable prognosis in bladder urothelial carcinoma. The best separation is achieved by an expression cutoff at 6.6 TPM which divides the patients into two groups with 5% 5-year survival for patients with high expression versus 0% for patients with low expression, p-value: 2.15e-4. Immunohistochemical staining using an antibody targeting MYO6 (CAB010762) shows a differential expression pattern in bladder urothelial 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
MYO6 - survival analysis

MYO6 - high expression

MYO6 - low expression

Table 2. The 20 genes with highest significance associated with a favorable prognosis in bladder urothelial carcinoma.

Gene
Description
Predicted location
mRNA (cancer)
p-value
Prognostic
MFSD6 Major facilitator superfamily domain containing 6 Membrane, Intracellular 17.6 1.06e-6 potential
BTG2 BTG anti-proliferation factor 2 Intracellular 122.3 2.26e-5 potential
FUCA1 Alpha-L-fucosidase 1 Intracellular 45.5 2.90e-5 potential
TBX3 T-box transcription factor 3 Intracellular 40.2 4.16e-5 potential
CPQ Carboxypeptidase Q Secreted, Intracellular 21.5 5.00e-5 potential
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The bladder urothelial carcinoma transcriptome

The transcriptome analysis shows that 71% (n=14329) of all human genes (n=20162) are expressed in bladder urothelial carcinoma. All genes were classified according to the bladder urothelial carcinoma-specific expression into one of five different categories, based on the ratio between mRNA levels in bladder urothelial carcinoma 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 bladder urothelial carcinoma as well as in all other cancer tissues.

169 genes show some level of elevated expression in bladder urothelial carcinoma 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 bladder urothelial carcinoma.

Distribution in the 31 cancers
Detected in singleDetected in someDetected in manyDetected in all Total
Specificity
Cancer enriched 45100 19
Group enriched 023394 66
Cancer enhanced 1024428 84
Total 14529112 169

Additional information

The majority of patients with urothelial cancer present symptoms of hematuria (blood in the urine) and/or dysuria (painful urination). Urothelial cancer most commonly arises in the urinary bladder, but can develop in the renal pelvis, ureters or urethra.

Papillary tumors appear in cystoscopy with variable size, ranging from minute excrescences to large, cauliflower like tumors protruding into the urinary bladder lumen. Histologically papillary tumors are characterized by tall and branched papillae that are usually covered by several layers of urothelial tumor cells.

Sarcomatoid (sarcoma and carcinoma features) variants of urothelial carcinoma exist and squamous cell carcinomas and adenocarcinomas can develop in the urinary bladder. Squamous cell carcinoma in the urinary bladder accounts for approximately 5% of all cancers in the urinary bladder. However, in areas where schistosomiasis is endemic, squamous cell carcinomas account for approximately 75% of all bladder carcinomas.

Urothelial cancer is classified with respect to surgical stage at time for diagnosis and tumor grade based on histology. Staging of urothelial cancer defines a tumor as cancer in situ, non-invasive, invasive in the lamina propria or invasive into muscular bladder wall. The TNM-based classification provides important prognostic information and guides further treatment. In addition, important prognostic information can also be obtained through the grading of the tumor based on morphological features. Tumor cells vary in atypical appearance and are graded according to the degree of nuclear atypia into four different grades, including urothelial neoplasm of low malignant potential. The most malignant tumors are of grade 3, and exhibit at least focal areas of high-grade nuclear atypia and common mitotic figures. Urothelial carcinoma grade 3 represents a tumor with more aggressive behavior and increased risk for recurrence and metastatic spread.

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

Habuka M et al., The Urinary Bladder Transcriptome and Proteome Defined by Transcriptomics and Antibody-Based Profiling. PLoS One. (2015)
PubMed: 26694548 DOI: 10.1371/journal.pone.0145301

Histology dictionary - Urothelial cancer