Transition from in situ to invasive testicular germ cell neoplasia is associated with the loss of p21 and gain of mdm-2 expression

Introduction: The tumor suppressor gene p53 has been shown to transcription ally regulate expression of the cell cycle dependent kinase inhibitor p21. p53 is in turn regulated by the ubiquitin ligase mouse double minute-2 (mdm -2). We have set out to examine p21 expression in testicular germ cell tumo rs and its relationship with p53 and mdm-2 expression. Methods: Immunohisto chemical analysis was performed on formalin-fixed paraffin-embedded tissue for p53, p21, and mdm-2 in 31 testicular germ cell tumors, which included 1 7 pure seminomas and 14 mixed germ cell tumors composed predominantly of em bryonal carcinoma. Twenty-seven cases contained adjacent areas of intratubu lar germ cell neoplasia (ITGCN), Results: 17 out of 17 seminomas and 14 out of 14 embryonal carcinomas expressed p53 in both ITGCN and the invasive tu mor. In contrast, none of the 17 seminomas and only 2 of 14 embryonal carci nomas revealed positive staining for p21 protein. p21 expression was noted in 18 of 27 cases (67%) of ITGCN, and in 16 of these cases (89%) the corres ponding invasive tumor had lost p21 expression. In nine additional cases p2 1 expression was absent in both the invasive and intratubular tumor, mdm-2 expression was present in 8 out of 17 (47%) seminomas and 13 out of 14 (93% ) embryonal carcinomas but was present in only 2 out of 27 (7%) cases of IT GCN. Statistically significant associations for loss of p21 and gain of mdm -2 expression in invasive tumors were present (P < .0001). Conclusions: The co-expression of p53 and p21 in ITGCN is consistent with preservation of p 53-directed induction of p21. The loss of p21 expression in invasive tumors suggests a disruption of the p53 regulatory pathway. The inverse correlati on of p21 and mdm-2 expression in both ITGCN and invasive tumors could indi cate that loss of the functional p53 regulatory pathway may be correlated w ith the onset of mdm-2 expression. These results raise the possibility that the loss of p21 expression may be associated with the development of invas ive germ cell tumors from ITGCN. Persistent p53 expression in the presence of mdm-2 suggests that in testicular germ cell tumors, while mdm-2 can bloc k the transactivation potential of p53, it can no longer target p53 for deg radation.