We also show that analysis of mutations in VHL using our workflow provides valuable insights into the effects of mutations, and their links to the risk of developing renal carcinoma.
VHL-deficient clear cell renal cell carcinomas (ccRCC), the most common form of kidney cancer, express transcripts derived from the novel human endogenous retrovirus HERV-E (named CT-RCC HERV-E).
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma.
Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome.
Clear cell renal cell carcinoma (ccRCC) is the major subtype of kidney cancer that is characterized by frequent inactivation of the von Hippel-Lindau (VHL) gene in 80-90% of the tumors.
Mutations in FH, resulting in loss of enzyme activity, predispose affected individuals to a rare cancer, hereditary leiomyomatosis and renal cell cancer (HLRCC), characterised by benign smooth muscle cutaneous and uterine tumours (leiomyomata) and an aggressive form of collecting duct and type 2 papillary renal cancer.
It exhibits a different molecular signature than clear-cell carcinoma and is typically not associated with mutations in the VHL (von Hippel-Lindau) tumor suppressor gene. pRCC is less responsive to modern drugs introduced in the management of kidney cancer in the past decade.
Patients with germline fumarate hydratase (FH) mutation are predisposed to develop aggressive kidney cancer with few treatment options and poor therapeutic outcomes.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant disorder in which germline mutations of fumarate hydratase (FH) gene confer an increased risk of cutaneous and uterine leiomyomas and renal cancer.
Somatic mutations or loss of expression of tumor suppressor VHL happen in the vast majority of clear cell Renal Cell Carcinoma, and it's causal for kidney cancer development.
Renal cancer is resistant to conventional chemotherapy and radiotherapy but increased understanding of the underlying tumour biology is leading to the use and development of targeted therapies, such as tyrosine kinase inhibitors targeting pathways downstream of the von Hippel Lindau tumour suppressor gene.
Several therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials, including the use of agents such as metformin, which would reverse the inactivation of AMPK, approaches to inhibit glucose transport, lactate dehydrogenase A (LDHA), the antioxidant response pathway, the heme oxygenase pathway, and approaches to target the tumor vasculature and glucose transport with agents such as bevacizumab and erlotinib.
Fumarate hydratase (FH)-deficient kidney cancer undergoes metabolic remodeling, with changes in mitochondrial respiration, glucose, and glutamine metabolism.
While seven FDA-approved agents that target the VHL pathway have been approved for the treatment of patients with advanced kidney cancer, further genomic studies, such as whole genome sequencing, gene expression patterns, and gene copy number, will be required to gain a complete understanding of the genetic basis of kidney cancer and of the kidney cancer gene pathways and, most importantly, to provide the foundation for the development of effective forms of therapy for patients with this disease.
Generalized cellular hypoxia (in sickle cell disease) or pseudohypoxia (in tumors with fumarate hydratase and von Hippel-Lindau mutations or epigenetic silencing) may act alone or in concert at the level of medullary tubular epithelium to promote development of this rare type of renal carcinoma, which could then be genetically reclassified as either fumarate hydratase-associated renal carcinomas or high-grade clear cell renal cell carcinomas.
The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels.
This review aims to focus on pathways in renal cancer (VHL/HIF, mTOR, c-MYC, c-MET, and immune response) in the respective tumor subtypes, accounting for the effects of targeted therapies and providing the framework to search for relevant predictive biomarkers and propose new trials.
As part of the French National Cancer Institute (INCa) 'Inherited predispositions to kidney cancer' network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic).
Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) causes the most common form of kidney cancer. pVHL is part of a complex that polyubiquitinates the alpha subunit of the heterodimeric transcription factor HIF.