The renal cancer 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 renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma and 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 renal cancer proteome using TCGA transcriptomics data and antibody-based protein data. 6075 genes are suggested as prognostic based on transcriptomics data from 877 patients; 3323 genes are associated with unfavorable prognosis and 2752 genes are associated with favorable prognosis.

TCGA data analysis

In this metadata study, we used data from TCGA where transcriptomics data was available from 877 patients in total, 64 patients with chromophobe renal cell carcinoma (KICH), 528 clear cell kidney carcinoma (KIRC) and 285 papillary kidney carcinoma (KIRP). The total dataset included 286 females and 591 males. Most of the patients (651 patients) were still alive at the time of data collection. The stage distribution was stage i) 452 patients, stage ii) 103 patients, stage iii) 187 patients, stage iv) 103 patients and 32 patients with missing stage information.

Unfavorable prognostic genes in renal cancer

For unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 3323 genes associated with an unfavorable prognosis in renal cancer. 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 renal cancer. The best separation is achieved by an expression cutoff at 28.2 fpkm which divides the patients into two groups with 40% 5-year survival for patients with high expression versus 75% for patients with low expression, p-value: 0.00e+0. Immunohistochemical staining using an antibody targeting CKAP4 (HPA000792) shows a differential expression pattern in renal cancer samples.

p<0.001
CKAP4 - survival analysis
CKAP4 - high expression
CKAP4 - low expression

BID is another gene associated with an unfavorable prognosis in renal cancer. The best separation is achieved by an expression cutoff at 6.8 fpkm which divides the patients into two groups with 49% 5-year survival for patients with high expression versus 75% for patients with low expression, p-value: 3.50e-13. Immunohistochemical staining using an antibody targeting BID (HPA000722) shows a differential expression pattern in renal cancer samples.

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

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

Favorable prognostic genes in renal cancer

For favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 2752 genes associated with a favorable prognosis in renal cancer. 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 renal cancer. The best separation is achieved by an expression cutoff at 55.7 fpkm which divides the patients into two groups with 78% 5-year survival for patients with high expression versus 62% for patients with low expression, p-value: 1.45e-5. Immunohistochemical staining using an antibody targeting BBOX1 (HPA007600) shows a differential expression pattern in renal cancer samples.

p<0.001
BBOX1 - survival analysis
BBOX1 - high expression
BBOX1 - low expression

TMEM72 is another gene associated with a favorable prognosis in renal cancer. The best separation is achieved by an expression cutoff at 9.3 fpkm which divides the patients into two groups with 76% 5-year survival for patients with high expression versus 65% for patients with low expression, p-value: 1.01e-4. Immunohistochemical staining using an antibody targeting TMEM72 (HPA062907) shows a differential expression pattern in renal cancer samples.

p<0.001
TMEM72 - survival analysis
TMEM72 - high expression
TMEM72 - low expression

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

The renal cancer transcriptome

The transcriptome analysis shows that 72% (n=14384) of all human genes (n=20090) are expressed in renal cancer. All genes were classified according to the renal cancer-specific expression into one of five different categories, based on the ratio between mRNA levels in renal 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 renal cancer as well as in all other cancer tissues.

387 genes show some level of elevated expression in renal 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 renal cancer.

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