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Transitional Cell Carcinoma:
Transitional cell carcinoma (TCC) is also known as urothelial cell carcinoma (UCC) is a type of cancer that typically occurs in the urinary system: the kidney,urinary bladder, and accessory organs. It is the most common type of bladder cancer and cancer of the ureter, urethra, and urachus; it is the second most common type of kidney cancer.TCC arises from the transitional epithelium, a tissue lining the inner surface of these hollow organs. TCC can also be associated with the prostate. TCCs are often multifocal, with 30-40% of patients having more than one tumour at diagnosis. The pattern of growth of TCCs can be papillary, sessile (flat) or carcinoma-in-situ (CIS).The most common site of TCC metastasis outside the pelvis is bone (35%); of these bone metastases, 40% are in the spine
Causes:
1.Certain drugs such as cyclophosphamide and phenacetin are known to predispose to bladder TCC.
2.long term usage of Analgesics.
3.Radiation Exposure
4.Somatic Mutation like Deletion of Chromosome 9p,9q,11p,17p,13q,14q and over expression of RAS (oncogene) and Epidermal growth factor receptor(EGFR).
5. Cigarette smoke
Genetics of TCC:
Genetics of TCC has advanced dramatically during the past few years. Present understanding includes a model for the molecular pathogenesis of the disease and an extensive repertoire of genes and loci known to be genetically altered in TCC, some of which show great promise as predictive markers. Various approaches have been used to identify genes which are commonly altered in TCC.Two types of approach have yielded a considerable amount of information which may ultimately lead to the isolation of key genes. Loss of heterozygosity (LOH) analysis is the first approach which has been used extensively in human sporadic cancers to identify the likely location of relevant tumour suppressor genes. Inactivation of several known tumour suppressor genes involves loss of function of both alleles in a somatic cell. This commonly occurs via one large deletion which may involve an entire chromosome or chromosome arm and a second small alteration, often a small intragenic insertion, deletion or point mutation in the retained allele. The gross genetic event can be detected as loss of one allele at polymorphic loci within the region of interest. LOH analysis using PCR-based assays is a robust technique requiring only a small amount of template DNA, suitable for use on DNA extracted from paraffin-embedded material and many thousands of precisely mapped polymorphisms have been identified. Thus a screen of the entire genome using a few markers on each chromosome arm can be followed by high-density deletion mapping to pinpoint the critical chromosomal region involved. This so-called ‘common region of deletion’ is then searched for expressed sequences which can be assessed as candidate genes. The second approach which seems likely to lead to the identification of novel genes is the technique of comparative genomic hybridization (CGH). The technique is simple in concept; genomic DNA from tumour and normal cells is differentially fluorescently labelled, and the two probes are mixed and hybridized to normal metaphase spreads. Differences in representation of sequences in the tumour DNA are identified by position on the metaphase chromosomes as a decrease or increase in tumour label intensity. Deletions of large regions of DNA have been identified by this means and many of the regions of deletion previously identified by LOH analysis have been confirmed by CGH, although fine deletion mapping by CGH is not possible. Over-representation of specific regions of the genome can be identified similarly and CGH has proved to be particularly powerful at identifying regions of high level DNA amplification which may pinpoint the location of as yet unknown oncogenes.
Polymorphism in Fas (APO-1/CD95) Gene:
Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling. The key role of the Fas system in negative growth regulation has been studied mostly within the immune system, and somatic mutations of Fas in cancer patients have been described solely in lymphoid-lineage malignancies.Alterations of the Fasgene might lead to the loss of its apoptotic function and contribute to the pathogenesis of some bladder cancers.
Polymorphism in Metabolic Genes:
Because polymorphisms in the methyl group metabolism genes methylene-tetrahydrofolate reductase (MTHFR), methionine synthase (MS), and cystathione ß-synthetase(CBS) affect plasma homocysteine levels and intracellular concentrations of S-adenosylmethionine (SAM), they modify the susceptibility to cardiovascular diseases and cancer. Specifically, genome-wide decreased DNA methylation (‘hypomethylation’) in human cancers might be a consequence of decreased SAM levels. But , on their own, the MTHFR, MS and CBS genotypes do not appear to act upon susceptibility to TCC or influence the extent of DNA hypomethylation in this cancer.
Polymorphisms in DNA repair and metabolic genes:
Urinary bladder cancer is also associated with genetic polymorphisms in the xeroderma pigmentosum complementation group C (XPC), group D (XPD) and group G (XPG), X-ray repair cross-complementing group 1 (XRCC1) and group 3 (XRCC3), Nijmegen breakage syndrome 1 (NBS1), cyclin D1, methylene-tetrahydrofolate reductase (MTHFR), NAD(P)H dehydrogenase quinone 1 (NQO1), H-ras and glutathione S-transferase theta 1 (GSTT1) genes.
Polymorphisms in GSTM1 and GSTT1 genes:
GSTM1 and GSTT1 genes are potential risk modifiers for bladder cancer. GSTM1 genotype may also affect the clinicopathological tumor outcome deleted genotypes for GSTM1 and GSTT1 are prevalent in the general population, the identification of these individuals may provide a useful public health approach for early detection and prevention of environmental cancers.
Polymorphism in Interleukin-4 gene & intron-3:
Cytokines are signalling molecules contributing to the inflammatory response, and protect the body from pathogens and other environmental factors. Cytokines comprise several proteins that are key components in the pathogenesis of many diseases, including cancer. Interleukin-lß, located at chromosome 2q12, is a potent pro-inflammatory agent which is central in immunoregulation, fever, inflammation and cancer formation. Polymorphisms of the interleukin-1ß gene promoter region and exon 5 have been screened for their role in the occurrence and severity of rheumatoid arthritis and osteoporosis.Interleukin-4 also inhibits macrophage activation and might be involved in cancer formation. The interleukin-4 gene has been mapped to the q arm (q23–31) of chromosome 5, and is in a cluster of cytokine genes (interleukin-3, -5, -9, -13 and -15, granulocyte colony-stimulating factor, and interferon regulatory factor) . A polymorphism of the interleukin-4 gene is located in the third intron, and is composed of a 70-bp sequence of variable numbers of tandem repeats (VNTR). The interleukin-4 gene intron 3 polymorphism is associated with bladder cancer and is a potential genetic marker in screening for the possible causes of bladder cancer.
Destabilization of chromosome 9:
The most frequent genetic alteration in transitional cell carcinoma of the urinary bladder (TCC) is loss of chromosome 9 which targets CDKN2A on 9p. While the high frequency of chromosome 9q loss in TCC may reflect destabilization of the chromosome related to hypomethylation of repetitive DNA.
Single Nucleotide Polymorphism:
Association between a C/A single nucleotide polymorphism of the E-cadherin gene promoter causes transitional cell carcinoma of the bladder.This single nucleotide polymorphism may serve as a prognostic marker of TCCB.
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