Genetic and immunophenotype analyses of TP53 in bladder cancer: TP53 alterations are associated with tumor progression

Erill N 1, Colomer A 1, Verdú M 2, Román R 1, Condom E 2, Hannaoui N 3, Banús JM 3, Cordón-Cardó C 4, and Puig X 1,2.

1BIOPAT, Grup Assistència, Barcelona; 2HISTOPAT Laboratoris, Barcelona; 3ICUN, Barcelona; and 4Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York.

Altered p53 status is a frequent event in bladder cancer and reported to have prognostic significance. We studied the TP53gene and its product in 76 patients affected with urinary bladder carcinomas by immunohistochemistry (mAb DO-7), polymerase chain reaction-single strand conformational polymorphism (exons 4-8) followed by direct sequencing of shifted bands, and loss of heterozygosity in 17p (p53CA). H-RAS mutations were also studied. The receiver operating characteristic curve and the logistic-regression analysis were used to evaluate the validity of immunohistochemistry in predicting TP53mutations. A p53 positive nuclear phenotype was defined by a cutoff of 20% tumor cells being immunoreactive and was found in 23 cases; while TP53 mutations were detected in 22 cases, four of them with a negative p53 phenotype. TP53deletions were identified in 23 cases. No H-RAS gene mutations were observed. There was a significant association between phenotype and genotype results. Moreover, a significant association was observed between p53 status and tumor stage and grade, being alterations more common in high stage and high grade tumors (both c2 test; p<0.01). Deletion of 17p significantly correlated with tumor stage (p<0.01) and grade (p=0.01 allelic losses being more common in advanced disease. In sum, data from these studies suggest that genetic assays are necessary for the optimal determination of TP53alterations, mainly in tumors with a p53 negative phenotype, and especially in early stage tumors for which p53 status may assist in determining its progression to invasive disease. Since p53 alterations are significantly associated to clinicopathological features of poor prognosis, the inclusion of both p53 phenotype and TP53 mutation status into a predictive panel of tumor markers text-tp53 is recommended.

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Diagn Mol Pathol 2004; 13: 217-223