The kidney chromophobe 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. Chromophobe renal cell carcinoma is the third most common form of renal cell carcinoma. It has a distinct biology compared to the other subtypes of renal cell carcinoma and generally gives a better outlook for the patients.

Here, we explore the kidney chromophobe proteome using TCGA transcriptomics data and antibody-based protein data. 905 genes are suggested as prognostic based on transcriptomics data from 64 patients; 828 genes are associated with unfavorable prognosis and 77 genes are associated with favorable prognosis.

TCGA data analysis

In this metadata study we used data from TCGA where transcriptomics data was available from 64 patients with kidney chromophobe. The total dataset included 26 female and 38 males. Among the patients, 55 were still alive and 9 deceased at the time of data collection. The stage distribution was stage i) 19 patients, stage ii) 25 patients, stage iii) 14 patients, and stage iv) 6 patients.

Unfavorable prognostic genes in kidney chromophobe

For unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 828 genes associated with an unfavorable prognosis in kidney chromophobe. In Table 1, the top 20 most significant genes related to an unfavorable prognosis are listed.

GBE1 is a gene associated with an unfavorable prognosis in kidney chromophobe. The best separation is achieved by an expression cutoff at 26 TPM which divides the patients into two groups with 63% 5-year survival for patients with high expression versus 97% for patients with low expression, p-value: 2.06e-4. Immunohistochemical staining using an antibody targeting GBE1 (HPA038073) 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
GBE1 - survival analysis

GBE1 - high expression

GBE1 - low expression

Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in kidney chromophobe.

Gene
Description
Predicted location
mRNA (cancer)
p-value
Prognostic
AURKA Aurora kinase A Intracellular 6.8 1.06e-6 potential
CDK4 Cyclin dependent kinase 4 Intracellular 72.6 2.54e-6 potential
PSME3 Proteasome activator subunit 3 Intracellular 33.8 2.94e-6 potential
COPS6 COP9 signalosome subunit 6 Intracellular 91.3 3.41e-6 potential
MRPL47 Mitochondrial ribosomal protein L47 Intracellular 34.5 4.81e-6 potential
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Favorable prognostic genes in kidney chromophobe

For favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 77 genes associated with a favorable prognosis in kidney chromophobe. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed.

RHCG is a gene associated with a favorable prognosis in kidney chromophobe. The best separation is achieved by an expression cutoff at 580 TPM which divides the patients into two groups with 95% 5-year survival for patients with high expression versus 56% for patients with low expression, p-value: 5.51e-5. Immunohistochemical staining using an antibody targeting RHCG (HPA041874) 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
RHCG - survival analysis

RHCG - high expression

RHCG - low expression

Table 2. The 20 genes with highest significance associated with a favorable prognosis in kidney chromophobe.

Gene
Description
Predicted location
mRNA (cancer)
p-value
Prognostic
TMEM233 Transmembrane protein 233 Membrane 4.5 8.27e-5 potential
NUTF2 Nuclear transport factor 2 Intracellular 70.1 2.42e-4 potential
MRPL46 Mitochondrial ribosomal protein L46 Intracellular 24.7 6.97e-4 potential
MT-ND1 Mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 Membrane 20294.1 7.45e-6 potential
ZFP36 ZFP36 ring finger protein Intracellular 52.2 8.64e-6 potential
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The kidney chromophobe transcriptome

The transcriptome analysis shows that 65% (n=13167) of all human genes (n=20162) are expressed in kidney chromophobe. All genes were classified according to the kidney chromophobe-specific expression into one of five different categories, based on the ratio between mRNA levels in kidney chromophobe 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 chromophobe as well as in all other cancer tissues.

434 genes show some level of elevated expression in kidney chromophobe 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 chromophobe.

Distribution in the 31 cancers
Detected in singleDetected in someDetected in manyDetected in all Total
Specificity
Cancer enriched 24224316 105
Group enriched 048458 101
Cancer enhanced 16508973 228
Total 4012017797 434

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