Effect of PTEN Gene Mutations and Environmental Risk Factors on the Progression and Prognosis of Bladder Cancer.

IntroductionBladder cancer is the most prevalent malignancy of the urinary tract, and the second most fre-quently diagnosed genitourinary malignancy among people living in the United States (1). About 90% of malignant tumors arising in the bladder are urothelial cell carcinomas (1). Urothe-lial bladder cancer constitutes two distinct clinical phenotypes. The common tumors are low grade and non-invasive which may relapse locally but development infrequently; other tumors which are muscle invasive often develop rapidly and have a poor prognosis (2).Environmental and genetic factors are the two factors associated with bladder cancer develop- ment. Understanding the etiology and identifying the risk factors are essential for the primary pre-vention of this deadly disease. The relationship between bladder cancer (BC) and smoking, occu-pational exposure to aromatic hydrocarbons, fami-ly history of cancer, chemotherapy and radio-therapy is quite likely (3). These factors result in uncontrolled growth of cell population, decreased cell death, invasion and metastasis, and may influ-ence the patient's prognosis. Recognition of the aggressive features of BC is very essential for suit-able management of this disease (4). Although several risk factors for relapse and progression of BC have been identified, their limited value has demonstrated the need for new molecular markers of BC outcomes (5, 6). While several people are exposed to bladder cancer risk factors, BC devel-ops in only a fraction of these individuals; there-fore, environmental or dietary factors or genetic backgrounds can be involved in susceptibility to bladder carcinogenesis (3).Accumulation of multiple genetic events leads to adult sporadic cancers. Many of these genetic events have been recognized in BC while others remain to be identified. The p53 gene on chromo-somal arm 17p, the Rb gene on chromosomal arm 13q, and the CDKN2a gene on chromosomal arm 9p are genetic factors known to contribute to bladder cancer. The recognition of chromosomal deletions suggest that additional suppressor loci are important in bladder carcinogenesis (7,8).PTEN/MMAC1 is a tumor suppressor gene lo-cated on human chromosome 10q23.3 that is found to be inactivated by homozygous deletion or point mutation in endometrial cancer, malig-nant gliomas and with a lower rate in prostate and breast cancer. Germ-line mutations in PTEN/MMAC1 have been associated with Cowden disease, an autosomal dominant cancer predisposition syndrome that increased the risk of skin, breast and thyroid tumors and occasional cases of other cancers including bladder cancer. The PTEN/MMAC1 gene contains 9 exons and encodes a 403-aa protein. PTEN gene acts as a phospholipid and phosphoprotein phosphatase. The tumor suppressor activity of PTEN is due to the action of its phosphatase and also its ability to negatively regulate phosphatidylinositol 3-kinase pathway. Following the expression of PTEN, cell cycle progression can be slowed down, cell migra-tion is reduced, and cell cycle arrest and apoptosis are induced.(9-12) Loss of PTEN activity leads to increased cell proliferation and reduced cell death (11).PTEN mutations have been observed in glioblas-tomas (12, 13), carcinomas of the prostate (13) and breast (14), endometrial carcinoma (15) and melanoma (16) in different studies; hence, PTEN can probably be a proper target of deletion in the-se cases. A similar trend has lately been found in bladder cancer cases (17).The rate of PTEN mutation in bladder cancer has not been adequately studied in Asia. We analyzed bladder cancers of 55 Iranian patients to study the role of PTEN mutation in tumor progression.Materials and MethodsTumor SpecimensBladder tumor samples were obtained from individ-uals who underwent surgery at the Sina Hospital. A small piece of the surgical specimen was removed for molecular analysis and stored at -80 °C until DNA extraction. Of the 55 patients, 52 were males and 3 were females with the mean age of 64. …