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Renal Cell Carcinoma which is also known as Hypernephroma is a type of cancer that affects the kidney especially, the proximal convoluted tubules which play a major role in filtering the blood for wastes. Renal Cell Carcinoma accounts for 80% of all the types of genitourinary cancers which is also the most lethal. In the initial stages there are possibilities of treating them with normal surgical methods or immunotherapy, where as if the cancer is complicated it becomes resistant to chemotherapy and radiotherapy.
Renal cell carcinoma is a multifactorial genetic disorder which is also acquired due to environmental and lifestyle factors. The incidence of RCC is due to various types of mutations on genes such as PRCC, RCA1, IL6, HGF, MET, TSC1, TSC2, CA9, TFE3 and VHL. The mapping of genes and determining their role in development of RCC has been largely under study with various factors like ethnicity, family background etc., under consideration.
The VHL gene abbreviated Von-Hippel Lindau gene is one of the genes responsible for the incidence of Renal Cell Carcinoma. This gene encodes 213-amino acid protein called the ubiquitin proteasome system protein. There are two isoforms of this gene and its gene locus is 3p26 - 3p25. The VHL gene plays a major role in tumor suppression, oxygen-related gene expression, protein assembly and development of the central nervous system. The inherited form of VHL gene mutation causes Von-Hippel Lindau syndrome which leads to various diseases like renalÂ angioma,Â renal cell carcinoma, phaeochromocytoma and the somatic mutation of the gene causes renal cell carcinoma. The main reason for choosing this gene for study is that the incidence of renal cell carcinoma is sure in both cases whether the mutation is inherited or is somatic.
Consideration of various characteristics of the cohort samples is very important in genetic studies to confirm the frequency of incidence of a disorder irrespective of age, sex, geographical, ethinic and other variations.
The samples used under study in identifying the role of VHL gene by the Hapmap committee were the African ancestry in southwest USA, Utah residents from CEPH collection, Han Chinese from Beijing, Chinese in Metropolitan Denver, Colorado, Gujarati Indians in Houston, Texas., Japanese in Tokyo, Japan., Luhya in Webuye, Kenya., Mexican ancestry in Los Angeles, California., Maasai in Kinyawa, Kenya., Toscans in Italy, Yoruban in Ibadan and Nigeria. The cohort samples used by Hapmap seem to be vastly distributed across the world which confirms that the disease is not limited to certain geographical region or ethinicity.
In 2005 Results from the Netherlands cohort study by Kjeld P van Houwelingen et al., confirmed prevalence of VHL gene mutations in RCC patients. Their results also showed that RCC prevailed 61%, higher than other histological types. A total of 120,852 men and women samples were under study classified on VHL mutated and Wild type tumors. It was a comparative study showing the influence of the mutation on the gene.
In 2008 Results of research carried out by Michael L. Nickerson et al., in cohort samples from Romania, Poland, Russia, and Czech Republic confirmed VHL gene mutation as a causative of 82.4% of the patients which is the highest reported up to date. A total of 205 samples were checked and classified based on their age, sex, smoking habits, level of cancer affected, body mass index and hypertension.
Fine Mapping And Mapping methodology
Some of the processes carried out in mapping the VHL gene and finding mutations are PCR, DNA sequencing, MLPA - Â Multiplex Ligation-Dependent Probe Amplification and RFLP.
Sequencing is done for all the three exons of the gene to find all possible mutations. Eventhough epidemiological tests of cysts and other genetic tests were available linkage analysis and designing of suitable markers became important criteria for conformation of the gene. Since various other translocations are also available in the chromosome 3 it is likely that there may be two loci for renal cell carcinoma.
Therefore availability of flanking markers will make identifying the VHL gene carriers easier in patients showing manifestations of the disease.
B. R. SEIZINGER et al. published a paper in 1990 about the designing of flanking markers which made diagnosis of the disease with specificity of the VHL gene much simpler.
They were able to develop large sequence hybridization probes. Its subset also mapped for 3p14-pter. This made a vast contribution in VHL identification showing their mendelinian inheritance. The markers also helped in determining the chromosomal position and constructing a fine structure linkage map.
The characterization of two cosmid probes or markers, 233E2 (D3S720) and 479H4 (D3S719), helped in linkage studies of both reference pedigrees and VHL patients. LINKMAP is one of the software's that was used in the analysis of two-point and multipoint linkage between 3p chromosome markers and VHL gene. Calculation of the logarithm of odds is an important factor which gave an approximate value of penetrance level of the gene. The VHL gene with relation to the RCC has a high penetrance level of 99% for all aged above 45 years.
Any change in thymine cluster in the ATT.TTT nucleotide region in the exon 2 at positions 147 and 148 of pVHL led to RCC in atleast 12% of the cases. Hiltrud Brauch et al., in their paper published in 2000 showed remarkable evidences in fine mapping of the mutations in VHL gene responsible for RCC.
The expression of VHL gene was found in mouse embryoblasts. The gene expression in human was inside the epithelial lining of the proximal tubules of the kidney where as the expression was dominant in lung, kidney and eyes of the mouse embryo. In human embryoblasts there was pronounced expression of the gene in areas associated with disease phenotypes. This paved a way for further researching in physiological role of the VHL gene and its mutation rate.
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