Cooperating events

Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)

  • Role of HIF in clear cell renal carcinoma
  • Cooperating events
  • Treatment of renal cell carcinoma: HIF antagonists
  • Treatment of renal cell carcinoma: mTOR inhibitors
  • Treatment of renal cell carcinoma: angiogenesis inhibitors
  • Treatment of renal cell carcinoma: tumor cell receptor tyrosine kinases
  • Other targets
  • Carbonic anhydrase and lactate dehydrogenase
  • Histone methylases and demethylases

It is clear that pVHL loss is an important, but not sufficient, step in renal carcinogenesis. This is most clearly demonstrated by studies of the natural history of von Hippel-Lindau disease. Patients with von Hippel-Lindau disease can develop hundreds of premalignant renal cysts, very few of which will go on to become clear cell renal carcinomas [67, 136] (Fig. 3.2). This bottleneck presumably reflects the requirement for additional genetic events, occurring stochastically, to fully transform renal epithelial cells. Indeed, a number of nonrandom genomic abnormalities have been described in clear cell renal carcinoma including, most notably, 5q amplification and 14q loss [6, 137–143] (Fig. 3.2). The triad of 3p loss, 14q loss, and 5q gain is a signature of clear cell renal carcinoma, and some clear cell renal carcinomas have unbalanced translocations involving 3p and 5q that result in loss of 3p and gain of 5q sequences [60, 144–150].

__Kidney Cancer_ Principles and Practice-Springer International Publishing (2015) 3.2

Fig 3.2. Development of renal cell carcinoma in VHL patients. VHL patients are VHL heterozygotes, having one normal VHL allele and one defective allele. Loss of the remaining normal allele in kidney cells, occurring stochastically, leads to the development of preneoplastic renal cysts. A minority of such cysts will ultimately accumulate additional genetic changes and become clear cell renal carcinomas. Such genetic changes include gain of 5q, loss of 14q, as well as intragenic mutations of specific genes such as PBRM1 or BAP1

Loss of chromosome 3p, which harbors the VHL tumor suppressor gene, is the most common genetic event in kidney cancer. Chromosome 3p has been suspected for many years, however, to contain at least one additional kidney cancer suppressor gene. Indeed, it is now clear that 3p harbors several renal cancer suppressor genes other than VHL including PBRM1, which encodes the BAF180 chromatinassociated protein; SETD2, which encodes a histone H3 lysine 36 methyltransferase; and BAP1, which encodes a ubiquitin hydrolase [82, 151–156] (Fig. 3.3). PBRM1 is, after VHL, the most frequently mutated gene in clear cell renal carcinoma. PBRM1 and BAP1 mutations are largely mutually exclusive and appear to define clinically distinct subgroups of renal cancers [152, 157, 158].

As described above, HIF1a is a likely target of the 14q deletions in VHL-/clear cell renal carcinomas. These deletions are very large, however, suggesting there are additional renal cancer suppressor genes located at 14q. It should also be noted that most 14q deleted VHL-/clear cell renal tumors (in contrast to cell lines) appear to retain a wild-type HIF1a allele [60]. This suggests that HIF1a is a haploinsufficient clear cell renal carcinoma suppressor and that loss of the remaining allele is associated with tumor progression in vivo or establishment of cell lines ex vivo.

SQSTM1, encoding p62, appears to be one of the renal carcinoma 5q oncogenes [159]. Increased expression of p62 promotes the growth of VHL-/renal carcinoma cells in cell culture and tumor xenograft assays and increases their resistance to redox stress [159]. p62 plays important roles in autophagy and also signals to renal carcinoma relevant proteins including NRF2, NFkB, and mTOR [160–162].

Sequencing of kidney cancer genomes has identified additional genes that, when mutated, contribute to renal carcinogenesis including several more genes linked to chromatin regulation such as JARID1C (also known as KDM5C), which encodes a histone H3 lysine 4 demethylase; UTX (KMD6A), which encodes a histone H3 lysine 27 demethylase; and ARID1A, a component of a chromatin remodeling complex [82, 151–156, 163]. Notably, many histone demethylase genes are themselves transcriptionally induced by HIF [164–169]. It is possible that their inappropriate expression pursuant to VHL loss alters chromatin structure and creates the selection pressure to mutate specific chromatin regulators.

__Kidney Cancer_ Principles and Practice-Springer International Publishing (2015) 3.3

Fig 3.3. Chromosome 3p harbors multiple renal cancer suppressors. Biallelic inactivation of the VHL tumor suppressor gene on chromosome 3p, usually as the result of intragenic mutation (indicated by the asterisk) followed by loss of the remaining wild-type allele because of a gross 3p deletion, is a critical early event in most clear cell renal carcinomas. The 3p deletions in clear cell renal carcinoma typically span VHL, on 3p25, as well as the additional renal cancer suppressors SETD2, BAP1, and PBRM1 on 3p21. As a result, subsequent intragenic mutations of these genes deprive renal cells of their wild-type protein products (for illustrative purposes PBRM1 is shown to be mutated)

Genes linked to the mTOR pathway including PIK3CA, PTEN, TSC1, TSC2, and MTOR itself are occasionally mutated in clear cell renal carcinomas [7, 82, 152, 155, 156]. Preliminary data suggest that such mutations identify a subset of renal cell carcinoma patients more likely to derive significant benefit from TORC1 inhibitors [170].

The NFE2L gene, encoding NRF2, and the NRF2-negative regulator KEAP1 are occasionally mutated in clear cell renal carcinoma [82, 159]. Such mutations appear to be mutually exclusive with higher level SQSTM1 amplification [159]. Genes involved in the response to DNA damage, including p53, MDM4, and ATM, are also occasionally mutated in clear cell renal carcinoma [7, 82, 155, 156]. p53 loss cooperates with Vhl loss in mouse models to promote renal carcinogenesis [171].

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