Tumorigenic pathways in low-stage bladder cancer based on p53, MDM2 and p21 phenotypes

Our aim was to determine whether the pattern of expression of the interrela ted proteins p53, MDM2 and p21 could shed light on the etiopathogenic mecha nisms of superficial bladder tumors. Protein expression was detected by imm unohistochemistry (IHC) using monoclonal antibodies (MAbs) Pab 1801 for p53 , 1F2 for MDM2 and EA10 for p21 on 269 newly diagnosed bladder tumors (214 pfa and 55 pT1; 93 grade 1, 145 grade 2 and 31 grade 3), While no p21 immun oreactivity was found in normal urothelium, 85% of tumors were strongly p21 -positive. MDM2 was overexpressed in 44% of tumors, almost all being also p ositive for p21, p53 was overexpressed in 20% of cases: 66% of p53-positive tumors were also MDM2 positive. compared with only 38% of p53-negative tum ors. p53 mutations were studied by direct DNA sequencing in a subset of 24 high-grade tumors. Both MDM2. and p21 were less frequently expressed in p53 mutated tumors compared with tumors with a wild-type gene. Distinct phenot ypes were correlated with the frequency of poorly differentiated (grade 3) tumors. The most common phenotypes were p21(+)/MDM2(-)/p53(-) and p21(+)/MD M2(+)/p53(-) observed in 38% and 29% of tumors, respectively. Grade 3 tumor s were found in 4% and 8% of these 2 groups, in contrast with 30% frequency in p21(+)/p53(+) tumors (p = 0.002) regardless of their MDM2 phenotype. Fo ur of the 5 (80%) tumors that were p53-positive but negative for p21 were g rade 3. Our data suggest that several tumorigenic pathways for superficial bladder tumors can be reflected by the expression pattern of these 3 protei ns. (C) 2000 Wiley-Liss, Inc.