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Genetic Basis of Renal Cell Carcinoma

Created: 2/11/2006


Genetic Basis of Renal Cell Carcinoma (RCC)


  • Studies from early 1980’s observed that deletions and translocations of the short arm of chromosome 3 occur in sporadic, non-inherited kidney cancer
  • Loss of a segment of chromosome 3 could be an early event in the development of RCC
  • Lots of work on hereditary forms of RCC (with known chromosomal abnormalities) may lead to the development of new treatment strategies for the management of RCC

von- Hippel Lindau (VHL) syndrome

  • Rare autosomal dominant cancer syndrome
  • Patients develop retinal angiomas, haemangioblastomas of the cerebellum and spine, phaeochromocytomas, renal and pancreatic cysts
  • Approximately 50% bilateral, multifocal clear-cell RCC’s
  • The VHL tumour suppressor gene, located on the short arm of chromosome 3, responsible for this syndrome was identified in 1993
  • Undergoes a “two-hit” loss of function whereby both copies of the gene present in the tumour tissue have been inactivated by mutation or loss
  • Defects in the VHL gene appear to be responsible for approximately 60% of cases of sporadic clear-cell RCC.

VHL protein

  • The VHL protein is produced in this condition arises from the VHL gene
  • Functions as a tumour suppressor by binding to transcriptional activators of hypoxia-inducible genes, such as hypoxia-inducible factor-a (HIF-1a) and 2a (HIF-2a), thereby destabilising them
  • Promotes the ubiquitination and destruction of HIF-1a
  • In clear cell RCC loss of the VHL gene, leads to an increase in HIF-1a , resulting in overexpression of proteins normally seen with hypoxia, for example vascular endothelial growth factor (VEGF), transforming growth factor-a (TGF-a) and ß (TGF-ß), and platelet derived growth factor-ß (PDGF- ß)
  • Increased levels of VEGF, PDGF-B, and TGF-ß stimulate tumour angiogenesis resulting in the delivery of additional oxygen and nutrients promoting tumour cell growth
  • Increase in TGF-a promotes tumour-cell proliferation and survival via activation of the epidermal growth factor receptor

Hereditary papillary renal carcinoma (HPRC)

  • HPRC is an autosomal dominant condition
  • Associated with multifocal, bilateral type I papillary RCC’s
  • Causative gene is the proto-oncogene c-MET, located on the long arm of chromosome 7
  • The c-MET gene encodes MET, a tyrosine kinase receptor which is normally activated by hepatocyte growth factor and regulates tyrosine kinase growth hormones and epithelial proliferation and differentiation
  • In HPRC the c-MET gene undergoes “gain of function” mutations which convert it from the usual autoinhibited state to an activated state
  • Chromosome 7 which contains the mutated gene is then duplicated which increases the gene dose
  • NB Only a small proportion of sporadic papillary RCC’s are associated with mutations in the MET gene. However, it may still play a significant role in light of the observation that in 75% of cases of sporadic papillary RCC there is duplication of chromosome 7

Hereditary leiomyomatosis and renal-cell cancer syndrome

  • Autosomal dominant condition
  • Individuals affected are at risk of developing cutaneous and uterine leiomyomas and papillary RCC
  • Primarily Type 2 papillary RCC’s
  • Tumours tend to be unilateral, solitary, metastasise early and are the most aggressive of the familial types
  • It is loss of the gene encoding the Krebs cycle enzyme, fumarate hydratase, which is lost in this condition

Birt-Hogg-Dube syndrome (BHD)

  • Rare autosomal dominant cancer syndrome
  • Patients develop fibrofolliculomas (hair follicle hamartomas) of the face and neck, pulmonary cysts and renal tumours
  • The BHD gene encodes the protein folliculin, a suspected tumour suppressor gene, and is found on the short arm of chromosome 17
  • Approximately 15% of affected individuals develop multiple renal tumours
  • They can be bilateral, multifocal, malignant and metastasise
Tumours are mainly chromophobe RCC’s, or mixed chromophobe-oncocytomas. NB Occasionally, papillary or clear cell tumours can arise
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