The kidney renal clear cell carcinoma proteome

Most renal cancers are renal cell carcinoma, which is almost exclusively cancer of adults and it is two to three times more common in males than in females. It is the ninth most common cancer in men and 14th most common in women worldwide. The clinical course is highly unpredictable and recurrence more than ten years after the initial resection of a primary tumor is not uncommon. Several cases present as metastatic carcinomas of unknown primary origin. Although smoking, industrial chemicals and obesity have been implicated as risk factors, in most cases the underlying carcinogenic source is unknown.

Renal cell carcinoma consists of a family of carcinomas which are derived from the epithelium of renal tubules. The most frequent forms are clear cell, papillary and chromophobe renal cell carcinoma, as well as collecting duct carcinoma. Approximately two thirds of all renal cell carcinomas are clear cell renal cell carcinomas and are signified by the appearance of tumor cells with abundant clear cytoplasm. Tumors can arise anywhere in the renal cortex and are typically surrounded by a fibrous pseudocapsule.

Here, we explore the kidney renal clear cell carcinoma proteome using TCGA transcriptomics data and antibody-based protein data. 8139 genes are suggested as prognostic based on transcriptomics data from 521 patients; 1149 genes are associated with unfavorable prognosis and 7005 genes are associated with favorable prognosis.

TCGA data analysis

In this metadata study we used data from TCGA where transcriptomics data was available from 521 patients with kidney renal clear cell carcinoma. The total dataset included 181 female and 340 males. Among the patients, 350 were still alive and 171 deceased at the time of data collection. The stage distribution was stage i) 259 patients, stage ii) 56 patients, stage iii) 122 patients, stage iv) 81 patients and 3 patients with missing stage information.

Unfavorable prognostic genes in kidney renal clear cell carcinoma

For unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 1149 genes associated with an unfavorable prognosis in kidney renal clear cell carcinoma, among these potential prognostic genes there are 253 genes that were validated in a separate study. In Table 1, the top 20 most significant genes related to an unfavorable prognosis are listed.

CKAP4 is a gene associated with an unfavorable prognosis in kidney renal clear cell carcinoma in two separate independent cohorts. The best separation is achieved by an expression cutoff at 37 TPM which divides the patients into two groups with 41% 5-year survival for patients with high expression versus 70% for patients with low expression, p-value: 1.75e-9. The TCGA data analysis was validated in a separate study with the p-value: 1.55e-5. Immunohistochemical staining using an antibody targeting CKAP4 (HPA000792) shows a differential expression pattern in renal 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 9101112
CKAP4 - survival analysis

CKAP4 - high expression

CKAP4 - low expression

TLCD1 is another gene associated with an unfavorable prognosis in kidney renal clear cell carcinoma in two separate independent cohorts. The best separation is achieved by an expression cutoff at 5 TPM which divides the patients into two groups with 52% 5-year survival for patients with high expression versus 74% for patients with low expression, p-value: 8.14e-10. The TCGA data analysis was validated in a separate study with the p-value: 8.40e-4. Immunohistochemical staining using an antibody targeting TLCD1 (HPA042366) shows a differential expression pattern in renal 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 9101112
TLCD1 - survival analysis

TLCD1 - high expression

TLCD1 - low expression

Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in kidney renal clear cell carcinoma.

Gene
Description
Predicted location
mRNA (cancer)
p-value
Prognostic
NUF2 NUF2 component of NDC80 kinetochore complex Intracellular 1.5 3.36e-14 validated
MXD3 MAX dimerization protein 3 Intracellular 3.2 1.28e-13 validated
PLXNB3 Plexin B3 Membrane, Intracellular 1.4 9.60e-12 validated
SPC24 SPC24 component of NDC80 kinetochore complex Intracellular 3.2 1.14e-11 validated
MC1R Melanocortin 1 receptor Membrane 2.6 2.37e-11 validated
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Favorable prognostic genes in kidney renal clear cell carcinoma

For favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 7005 genes associated with a favorable prognosis in kidney renal clear cell carcinoma, among these potential prognostic genes there are 1683 genes that were validated in a separate study. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed.

BBOX1 is a gene associated with a favorable prognosis in kidney renal clear cell carcinoma in two separate independent cohorts. The best separation is achieved by an expression cutoff at 104 TPM which divides the patients into two groups with 77% 5-year survival for patients with high expression versus 49% for patients with low expression, p-value: 1.03e-11. The TCGA data analysis was validated in a separate study with the p-value: 6.80e-5. Immunohistochemical staining using an antibody targeting BBOX1 (HPA007600) shows a differential expression pattern in renal 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 9101112
BBOX1 - survival analysis

BBOX1 - high expression

BBOX1 - low expression

TMEM72 is another gene associated with a favorable prognosis in kidney renal clear cell carcinoma in two separate independent cohorts. The best separation is achieved by an expression cutoff at 2.6 TPM which divides the patients into two groups with 69% 5-year survival for patients with high expression versus 51% for patients with low expression, p-value: 4.31e-5. The TCGA data analysis was validated in a separate study with the p-value: 3.45e-4. Immunohistochemical staining using an antibody targeting TMEM72 (HPA062907) shows a differential expression pattern in renal 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 9101112
TMEM72 - survival analysis

TMEM72 - high expression

TMEM72 - low expression

Table 2. The 20 genes with highest significance associated with a favorable prognosis in kidney renal clear cell carcinoma.

Gene
Description
Predicted location
mRNA (cancer)
p-value
Prognostic
FUCA1 Alpha-L-fucosidase 1 Intracellular 59.5 0.00e+0 potential
AUH AU RNA binding methylglutaconyl-CoA hydratase Intracellular 18.1 4.00e-15 validated
SOWAHB Sosondowah ankyrin repeat domain family member B Intracellular 3.7 5.88e-15 validated
PTPRB Protein tyrosine phosphatase receptor type B Membrane, Intracellular 22.1 9.44e-15 validated
PAFAH2 Platelet activating factor acetylhydrolase 2 Intracellular 8.9 1.08e-14 validated
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The kidney renal clear cell carcinoma transcriptome

The transcriptome analysis shows that 69% (n=13835) of all human genes (n=20162) are expressed in kidney renal clear cell carcinoma. All genes were classified according to the kidney renal clear cell carcinoma-specific expression into one of five different categories, based on the ratio between mRNA levels in kidney renal clear cell 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 kidney renal clear cell carcinoma as well as in all other cancer tissues.

368 genes show some level of elevated expression in kidney renal clear cell 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 kidney renal clear cell carcinoma.

Distribution in the 31 cancers
Detected in singleDetected in someDetected in manyDetected in all Total
Specificity
Cancer enriched 68513 32
Group enriched 0665714 137
Cancer enhanced 14347873 199
Total 20108140100 368

Additional information

Microscopically, clear cell renal cell carcinomas typically present a network of small blood vessels of uniform small caliber in addition to an abundant clear cytoplasm of tumor cells. The clarity of the cytoplasm is due to ample content of lipids and glycogen. Small and large cysts, hemorrhage and areas of necrosis are commonly found within the tumor. Of renal cell carcinomas, approximately 10-15% are papillary renal cell carcinomas, which are characterized by a predominantly papillary or tubulopapillary growth pattern. Chromophobe renal cell carcinoma accounts for approximately 5% of all renal cell carcinomas and is the least aggressive variant. Chromophobe renal cell carcinomas are characterized by the presence of large numbers of minute intracytoplasmic vesicles with a flocculent appearance in tumor cells. All renal cell carcinomas can exhibit sarcomatoid changes. Benign tumors in the kidney also exist as adenomas, which are smaller tumors (less than 0.5 cm in diameter) compared to renal cell carcinomas, and oncocytomas which are characterized by tumor cells displaying large, intensely eosinophilic and finely granular cytoplasm and rounded nuclei.

The extent of spread of the primary tumor is the dominating factor that determines prognosis and is also the basis for tumor staging according to the TNM system. Renal cell carcinomas frequently invade the renal venous system and metastasize via the hematogenic route. Metastases in regional lymph nodes without hematogenic spread to distant organs are uncommon. Renal cancer patients have a mortality rate of 1.8 per 100.000. Clinical symptoms include hematuria, pain and mass in the flank as well as systemic symptoms such as fever, malaise and anemia.

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 kidney transcriptome and proteome defined by transcriptomics and antibody-based profiling. PLoS One. (2014)
PubMed: 25551756 DOI: 10.1371/journal.pone.0116125

Histology dictionary - Renal cancer