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The genetic basis of kidney cancer: implications for gene-specific clinical management

Created: 26/7/2006


The genetic basis of kidney cancer: implications for gene-specific clinical management
Linehan WM, Grubb RL, Coleman JA, Zbar B, Walther MM
BJU Int 2005 March; 95 Suppl 2: 2-7


  • 24% of all cancer diagnoses are urological (In the USA)
  • Of cancer deaths 10% are urological
  • Incidence of kidney cancer has been increasing since 1970’s
  • Annual increase is 2.5%, with highest increases in black men and women[1]
  • Most common histological cancers
    • Clear cell (75%)
    • Type I papillary RCC (˜5%)
    • Type II papillary RCC (˜10%)
    • Chromophobe RCC and oncocytoma (˜10%)
  • Studies from early 80’s indicated loos of a segment on short arm of chromosome 3 in sporadic, non-inherited kidney cancer

Inherited forms of kidney cancer

  1. von Hippel-Lindau (VHL)- inherited form of clear cell
  2. hereditary papillary renal carcinoma (HPRC)- inherited form of type I papillary RCC
  3. hereditary leiomyoma renal cell carcinoma (HLRCC)- inherited form of type II papillary RCC
  4. Birt-Hogg-Dube syndrome (BHD)- risk of developing several different types of kidney cancer including chromophobe RCC and oncocytoma

VHL: Inherited clear cell RCC

  • Individuals are at risk of developing tumours in several organs including kidney
  • Renal carcinomas are clear cell and can be bilateral, multifocal and occur at an early age
  • Estimated that individuals are at risk of developing up to 600 RCC’s and 1100 cysts per kidney
  • VHL gene was identified on the short arm of chromosome 3 in 1993[2]
  • Type and location of VHL gene mutation determine clinical manifestations
  • Maranchie et al [3] found a higher incidence of RCC in patients with partial rather than complete VHL gene deletions
  • VHL gene appears to be the gene for clear cell RCC as mutations of VHL are found in a high proportion of patients with sporadic non-inherited cancer
  • VHL gene is a “two-hit”, loss of function tumour suppressor gene-in tumour tissue both copies of the gene are inactivated by mutation or loss
  • VHL protein forms a complex with other proteins and targets HIF which is a transcription factor regulating several downstream genes eg VEGF. When VHL is damaged (as in clear cell kidney cancer) these genes are expressed


  • Individuals are at risk of developing bilateral, multifocal type 1 papillary RCC
  • Disease is highly penetrant- if affected it highly likely that the individual will develop papillary kidney cancer
  • Patients are at risk of developing 3000 tumours per kidney
  • Kidney appears to be the only organ affected in HPRC
  • Tumours appear in 5th and 6th decade
  • Tumours are hard to detect with USS and may enhance poorly on CT, however CT has greater sensitivity
  • The gene for HPRC, the proto-oncogene c-Met, is located on the long arm of chromosome 7
  • Mutations are “gain-of-function” or activating mutations

BHD Syndrome

  • Hereditary cancer syndrome in which those affected are at risk of developing fibrofolliculomas, pulmonary cysts and renal tumours
  • Tumours are mainly chromophobe RCC, oncocytic neoplasms and oncocytoma
  • They can be bilateral, multifocal, malignant and metastasise
  • The BHD gene is found on the short arm of chromosome 17

Managing VHL, HPRC and BHD renal tumours

  • Surgical removal if tumour =3 cm
  • Observation and careful follow-up if <3cm
  • Aim is to preserve renal function as long as possible while minimising chance of metastasis
  • Radiofrequency ablation is being evaluated for small tumours


  • Those affected are at risk of developing cutaneous and uterine leiomyomas and papillary RCC
  • They are primarily Type 2 papillary RCC
  • Tumours tend to be unilateral, solitary, aggressive and metastasise early
  • The gene is that for the Krebs cycle enzyme, fumarate hydratase
  • Further
  • Work is required to determine best imaging modality and treatment option

1. Chan, W., et al., Rising incidence of renal cell cancer in the United States. JAMA, 1999. 281: p. 1628-1631.

2. Latif, F. and e. al, Identification of the von Hippel-Lindau disease tumour suppressor gene. Science, 1993. 260(1317-1320).

3. Maranchie, J. and e. al, Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location. Human Mutation, 2004. 23: p. 40-46.

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