Like cancers of the breast, colon and prostate, kidney cancer occurs in both a hereditary and a sporadic (non-hereditary) form. The year 2003 marked the 10th anniversary of the discovery of the VHL tumour suppressor gene, the first gene identified for hereditary RCC that is now known to be involved in approximately 80% of sporadic RCCs, accounting for some 2% of all adult neoplasma [153]. In many VHL families, the diagnosis of VHL can now be made at birth by detection of VHL gene mutations in blood cells. The finding of frequent VHL gene mutations in tumour tissue from patients with sporadic kidney cancer provides the opportunity for scientists to significantly improve methods for diagnosis of kidney cancer by detecting such mutations, either in tissue removed at surgery or by biopsy or, potentially, by searching for VHL gene mutations in the urine or circulating cells of patients with this disease.
In a study published in 1994, to elucidate the aetiological role of the VHL gene in human kidney tumourigenesis, Gnarra et al. analysed localised and advanced tumours from 110 patients with sporadic renal carcinoma for VHL mutations and loss of heterozygosity (LOH) [123]. VHL mutations were identified in 57% of clear cell renal carcinomas analysed and LOH was observed in 98% of those samples. The identification of VHL mutations in a majority of localised and advanced sporadic renal carcinomas indicates that the VHL gene plays a critical part in the origin of this malignancy [123].
In another study carried out by Brauch et al. in 2000 to investigate the role of somatic alterations for renal canceraetiology and prognosis, 227 sporadic renal epithelial tumours were analysed for mutations and hypermethylations in the VHL gene. Somatic
VHL mutations were identified by PCR, single-strand conformation polymorphism
analysis, and sequencing, and hypermethylations were identified by restriction enzyme digestion and Southernblotting. Frequencies of VHL alterations were established, andan association with tumour type or tumour type and tumour stage was evaluated. VHL mutations and hypermethylations were identified in 45% of clear cell renal cell carcinomas (CCRCCs). RCCs carrying VHL alterations showed, in nine cases (12%),
mutations at a hot spot involvinga thymine repeat (ATT.TTT) in exon 2. Tumour staging was criticalto the VHL mutation/hypermethylation detection rate in CCRCCs shown by separate evaluation of patients from medical centersin Münich, Heidelberg, and Mainz. The spectrum of pT119, pT2,and pT3 CCRCCs and the VHL mutation/hypermethylation
detection rate varied among these three groups. Altogether, VHL alterations were significantly associated with pT3 CCRCCs. This was the first evidence of frequent
somatic VHL mutations at a particular site within exon 2 and an association of VHL mutations/hypermethylationswith a standard prognostic factor.
The spectrum of VHL mutations is enormous. As already discussed, almost any nucleotide of the coding sequence may be affected by substitutions, deletions or insertions and other changes may involve methylation. Although most of these alterations seem distributed at random, some occur more frequently. For example, somatic mutationsin RCCs cluster within VHL exon 2 [123]. Also, RCCs of patientswith defined occupational exposure to a human carcinogen, i.e., the organic solvent trichloroethylene, show frequent cytosine to thymine (C→T) transitionsand/or a VHL hot spot mutation in exon 1 [154]. With the exception of patients with known environmental exposure for which non-randomVHL mutations may be linked to a specific carcinogen,
the originof frequent mutations at other sites remains elusive. The idea that non-random distribution of somatic VHL mutations not only originating endogenously but also from exposure to exogenous carcinogens, is supported by the observation of regional variations in RCC incidence.For example, for yet unknown reasons, the Bas Rhin region of Francehas one of the highest incidences of RCC in the world [155].Furthermore, on the molecular level, the findings of a widespectrum of somatic VHL mutation frequencies in patients from Europe, the United States, and Japan are unexplained. Therefore, comprehensive molecular and histo-pathological data analyses of patients from potentially high-risk areas may provide further clues to the aetiology of RCCs and the meaning of somatic VHLalterations.
In summary, the contribution of VHL mutation to onset of human RCC has been observed in hereditary and is now accepted to be involved in the most cases of sporadic RCCs. Current data shows that VHL mutations mainly occurred in clear cell renal cell carcinoma. Tumour-type specificity of VHL mutation suggests that different carcinogeneic mechanisms underlie different tumour types of RCC, and might determine different biological behaviours of tumours, e.g. invasiveness and metastasis. Finally, evidence exists, which suggests that the VHL mutation rate might be associated with advanced tumour stage of CCRCC.
19 "T" describes the primary tumour within the organ. A small "p" (p stands for pathology) before the T describes how the cancer cells
look under a microscope. pT1: The primary tumour is localised to tissue of origin. pT2: The tumour is found in tissue of origin, and has begun to invade the blood vessels or lymphatic vessels next to the tumour. pT3: The tumour has invaded further blood vessels.