Pathology and genetics of tumours of the urinary system and male genital organs

Although bladder cancers are very common, little is known about their molecular pathogenesis. In this study, invasive bladder cancers were evaluated for the presence of gene mutations in the p53 suppressor gene. Of 18 tumors evaluated, 11 (61 percent) were found to have genetic alterations of p53. The alterations included ten point mutations resulting in single amino acid substitutions, and one 24-base pair deletion. In all but one case, the mutations were associated with chromosome 17p allelic deletions, leaving the cells with only mutant forms of the p53 gene products. Through the use of the polymerase chain reaction and oligomer-specific hybridization, p53 mutations were identified in 1 to 7 percent of the cells within the urine sediment of each of three patients tested. The p53 mutations are the first genetic alterations demonstrated to occur in a high proportion of primary invasive bladder cancers. Detection of such mutations ex vivo has clinical implications for monitoring individuals whose tumor cells are shed extracorporeally.

https://science.sciencemag.org/content/sci/252/5006/706.full.pdf

Identification of p53 gene mutations in bladder cancers and urine samples

PTEN: life as a tumor suppressor.

Neoplastic diseases are characterized by uncoordinated cell growth. Cellular proliferation follows an orderly progression through the cell cycle, which is governed by protein complexes composed of cyclins and cyclin-dependent kinases. These complexes exert their regulatory function by phosphorylation of key proteins involved in cell cycle transitions, such as the product encoded by the retinoblastoma gene (pRB). Mutations and overexpression of cyclins and cyclin-dependent kinases, mainly cyclin D1 and Cdk4, have been reported and proposed to be oncogenic events. More recently, a new family of negative regulators functioning as Cdk-inhibitory molecules has been identified. Because of their recessive nature in cell cycle control and the fact that some of them are mutated in human tumors, it has been suggested that they may also function as tumor suppressor genes. It appears that the molecular networking of these proteins and complexes impact on two fundamental cell cycle regulators: p53 and pRB. Cross-talk pathways between these two nuclear proteins are being delineated, implying potential links between p53 and pRB in cell cycle control, apoptosis, and tumor progression. In addition, the high rate and mutation pattern of TP53 and RB in primary tumors have rendered them prototype tumor suppressor genes. Furthermore, detection of TP53 and RB mutations and altered expression of their encoded products appear to be of clinical significance, often correlating with prognosis, when identified in specific cancers. Based on these findings, new strategies are being developed in the emerging field of gene replacement-therapy.

Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia.

IN recent years, there have been important advances in our understanding of the biology of bladder cancer. They have been achieved with the use of new experimental models, the study of oncogenes in bladder cancer, and the demonstration of a wide range of functional heterogeneity in populations of morphologically identical bladder cancer cells. The development of new techniques of management — including diagnosis and staging, the use of intravesical chemotherapy and preemptive (neoadjuvant) intravenous chemotherapy, and the application of new monoclonal antibodies — appears to be yielding higher rates of response, prolonged disease-free survival, and perhaps even improved rates of . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199004193221607?listPDF=true

Biology and Management of Bladder Cancer

Nine cases of transitional cell carcinoma (eight from the urinary bladder and one from the ureter; six noninvasive and three invasive) were subjected to detailed cytogenetic analysis with a G-banding method. The synchronization of primary cultures with methotrexate for high-resolution banding was performed in five cases. In the remaining four cases, the chromosomes were obtained from short-term cultures after prolonged (16 hr) exposure to Colcemid. Two cases were near-tetraploid, one was hypotriploid, and six were near-diploid (three hyperdiploid and three hypodiploid). All but one case showed various structural abnormalities in the karyotype. The chromosomal changes ranged from the presence of only two abnormal chromosomes (markers) to complex karyotypes with as many as 15 markers. In most tumors, the origin of the marker chromosomes could be readily deciphered. The nonrandom chromosomal aberrations included: ( a ) an isochrosome of the short arm of chromosome 5 (three cases); ( b ) monosomy of chromosome 9 found in four cases (this was the sole abnormality in one case); ( c ) involvement of chromosome 8 as an isochromosome of the long arm (two cases) or loss of the short arm due to deletion (one case) or translocation (one case); and ( d ) interstitial deletion of chromosome 13 (three cases). Our results indicate that the formation of i(5p) and monosomy 9 may be the primary karyotypic changes in two subgroups of transitional cell carcinoma. Involvement of chromosomes 8 and 13, on the other hand, seems to be a result of secondary karyotypic evolution. Two invasive tumors showed the presence of secondary clones, with additional structural chromosome aberrations superimposed on those already existing in the main cell population. In both cases, the additional aberrations involved the short arm of chromosome 11, resulting in loss of genetic material from the short arm. The short arm of chromosome 11, is the putative site of an oncogene which has been isolated from human bladder carcinoma cell lines. Deletion of the 11p was also seen in one case of noninvasive transitional cell carcinoma localized in the ureter; the material from 11p was probably translocated to chromosome 13. These findings suggest that the loss of genetic material from the short arm of chromosome 11 is a secondary event in the karyotypic evolution of transitional cell carcinoma, probably related to the invasive behavior of the tumor.

http://cancerres.aacrjournals.org/content/canres/44/3/1257.full.pdf

Connolly Jg

Papers

Nonrandom chromosomal changes in transitional cell carcinoma of the bladder.