Insights into the Genetic Basis of the Renal Cell Carcinomas from The Cancer Genome Atlas

Abstract

The renal cell carcinomas, clear cell, papillary, and chromophobe, have recently undergone an unmatched genomic characterization by The Cancer Genome Atlas (TCGA). This analysis has revealed new insights into each of these malignancies, and underscores the unique biology of clear cell, papillary, and chromophobe renal cell carcinoma. Themes that have emerged include distinct mechanisms of metabolic dysregulation and common mutations in chromatin modifier genes. Importantly, the papillary renal cell carcinoma classification encompasses a heterogeneous group of diseases, each with highly distinct genetic and molecular features. In conclusion, this review summarizes renal cell carcinomas which represent a diverse set of malignancies, each with novel biological programs that define new paradigms for cancer biology.

Metabolic Alterations in Cancer and Their Potential as Therapeutic Targets

“…Mitochondrial DNA sequencing has revealed that many chRCC tumors have mutations in genes involved in the ETC complex I, particularly in MT-ND5 , and that these mitochondrial gene mutations also correlate with samples exhibiting an eosinophilic histological phenotype 24 . This phenotype also correlates with an increase in mitochondrial mass resulting from an accumulation of mitochondria, possibly in compensation for hindered mitochondrial functioning 9 . Thus, the metabolic profile of chRCC appears to be very different from that of other types of kidney cancer.…”

“…There are three main subtypes of renal cell carcinoma: clear cell (ccRCC), papillary (pRCC), and chromophone (chRCC), each distinguished by unique histology and driver mutations 9 . Interestingly, although the overall mutational burden is relatively low in RCC in comparison to many other tumor types 9 , the vast majority of mutations identified in these tumors are in some way involved in the cell's ability to sense or respond to nutrients, oxygen, iron, or energy, suggesting that metabolic pathway alterations are key drivers of proliferation in all subsets of RCC 10 . Mutations resulting in dysregulation of specific steps of glycolysis, the TCA cycle, and the ETC pathways have all been found in subtypes of RCC, illustrating the diversity of metabolic alterations that may contribute to tumorigenesis (Fig.…”

Papillary renal cell carcinomas rewire glutathione metabolism and are deficient in anabolic glucose synthesis

“…Currently, the MET pathway is the most common target for developing new treatments for pRCC, such as the MET kinase inhibitor Savolitinib, which interrupts angiogenesis (8). Type II has more likely mutations such as SETD2, NF2, and the inactivation of CDKN2A by mutation, deletion, or CpG island hypermethylation (5,9). Structural variants were observed in sporadic events, including duplications in EGFR and HIF1A, and deletions in SDHB, DNMT3A, and STAG2 (10).…”

“…Furthermore, type II pRCC was subdivided into three subtypes, based on distinct molecular and phenotypic features. pRCC type II tumors are more likely to metastasize (4), and FH mutations and DNA hypermethylation were found to be correlate with inferior prognosis (5,9). Hence, the hypermethylation group was termed "CpG island methylation phenotype" (CIMP), which additionally featured a metabolic shift known as the Warburg effect (5).…”

A New Chromatin–Cytoskeleton Link in Cancer

“…In the kidney, in addition to MRTs and RMCs, renal cell carcinoma (RCC) is also characterized by defects in chromatin modifiers. Over 95% of clear cell RCCs exhibit 3p loss, resulting in co-deletion of a cluster of chromatin modifier genes on the short arm of chromosome 3: the histone methyltransferase SETD2 , the SWI/SNF component PBRM1, and the histone deubiquitinase BAP1 (7, 8). Subsequent “second-hit” mutations in these genes result in loss-of-function, and contribute to progression of RCC, and in the case of SETD2 and BAP1 , are associated with aggressive tumors and the lethal phenotype (7, 9).…”