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The official name of the HRAS gene is "v-Ha-ras Harvey rat sarcoma viral homolog". This gene is responsible in providing instructions to create the H-Ras protein. The H-Ras protein has the ability to regulate cell division, through a process called signal transduction. This allows H-Ras to relay signals from the outside of the cell into the nucleus, initiating cell growth or division. The H-Ras protein is a GTPase (guanosine triphosphatase) activating proteins which converts GTP into GDP (guanosine diphosphate). This process is achieved when GTP binds to a transcription factor called elF2 and is later hydrolysed to form GDP. As a result, the HRAS gene is also an oncogene which has the potential to induce cancerous tumour cells. In particular, a mutated HRAS gene may cause bladder cancer. Tumours in the bladder begin as superficial wart-like growths called papillomas. If these enlarge, it can cause difficulty in urinating, haematuria (blood in the urine) and increased risked of urinary tract infection. Then if papillomas are left untreated, it can become cancerous.
Bladder cancer is the most common malignancy of the urinary tract, characterised by multiple growths that tend to recur in a more aggressive form. Bladder cancer occurs 2-3 times more often in men than in women and is more prevalent in urban that rural areas. The risk of bladder cancer increases with cigarette smoking, ingestion of phenacetin analgesics, and exposure to aniline dyes, beta-naphthylamine, mixtures of aromatic hydrocarbons, or benzidine and its salts, used in chemical, paint, plastics, rubber, textile, petroleum and wood industries and in medical laboratories. Other predisposing factors are chronic urinary tract infections, calculous disease and schistosomiasis.
Symptoms of bladder cancer include haematuria, frequent urination, dysuria and cystitis. Urinalysis, excretory urography, cystoscopy or transurethral biopsy is performed for diagnosis. There are three types of bladder cancers and are named according to the type of cells that become malignant. Although the majority of bladder malignancies are transitional cell carcinomas, small percentages are squamous cell carcinomas or adenocarcinomas.
Transitional cells carcinoma - A malignant, usually papillary tumour derived from transitional stratified epithelium occurring in the innermost tissue layer of the bladder.
Squamous cell carcinoma - A slow growing malignant tumour beginning in the squamous epithelium, after long term infection or irritation of the bladder.
Adenocarcinoma - Cancer that begins from a large group of malignant, epithelial cell tumours of glandular cells which may form after long-term irritation and inflammation of the bladder.
Superficial or multiple lesions may be treated by fulguration or open-loop resection. A segmental resection is usually performed if the tumour is at the dome or in a lateral wall of the bladder. Total cystectomy may be performed for an invasive lesion of the trigone, area formed by the two uretal orifices and the internal urethral orifice. Radiation therapy alone or with chemotherapy, such as intravesical BCG (Bacillus Calmette-Guerin immunotherapy) may also be curative, even in unresectable tumour growth. Medications that are often used as palliative are BCG, 5-fluoroauracil, thiotepa and adriamycin.
THE AFFECTED HRAS GENE
The HRAS gene is involved in regulating cell division. Somatic HRAS gene mutations can develop in a person's lifetime and are only present in certain cells; therefore bladder cancer cannot be inherited. A particular mutation allows bladder cancer to develop, which causes the amino acid glycine to be replaced with the amino acid valine at protein position 12. Consequently, the mutated H-Ras protein affects normal apoptosis and instead initiates uncontrollable cell proliferation, which leads to the formation of a tumour.
Furthermore, Costello Syndrome is characterised by delayed development and intellectual disability and is also caused by mutations in the HRAS gene. At least eight mutations in the HRAS gene have been identified, wherein an amino acid's location is changed on a critical region in the H-Ras protein. A common genetic change causes the amino acid glycine to be replaced with serine at protein position 12. Therefore, again causing uncontrolled cell proliferation but resulting in cancerous or non-cancerous tumours.
The HRAS gene is located on the negative short (p) arm of chromosome 11 at position 15.5 (figure 1). Therefore, the cytogenetic location of the HRAS gene is 11p15.5, and the molecular location is on chromosome 11: base pairs 532, 241 to 535, 549. This gene has seven exons. The HRAS gene regulatory elements include: STAT3, Max1, NF-kappaB1, c-Myc, Max, NF-kappaB, c-Myb, NF-1, ZID, CUTL1.
Orthologues and paralogues are subdivisions of homologous genes which are genes in similar structure. Paralogues are genes with a homologous structure located at different sites of the same individual, which indicates diverging from a process of gene duplication. The HRAS gene paralogues include: RALA2, RIT22, RERGL2, ERAS2, RERG2, NRAS2, REM22, KRAS2, RRAS22, REM12, RASL122, RIT12, RRAS2, RALB2, RRAD2, GEM2, RASL11A2, MRAS2, RASL11B2. Orthologues are genes in different species that are similar in their nucleotide sequences, suggesting they originated from a common ancestor. Therefore, the HRAS orthologues consist of: HRAS1 (dog: canis familiaris), HRAS1 (chimpanzee: Pan troglodytes), Hras1 (rat: Rattus norvegicus), Hras1,5 (mouse: Mus musculus), HRAS1 (chicken: Gallus gallus).