Transition from In Situ to Invasive Testicular Germ Cell Neoplasia is Associated with the Loss of p21 and Gain of mdm-2 Expression

Abstract

Introduction: The tumor suppressor gene p53 has been shown to transcriptionally 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 tumors and its relationship with p53 and mdm-2 expression. Methods: Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded tissue for p53, p21, and mdm-2 in 31 testicular germ cell tumors, which included 17 pure seminomas and 14 mixed germ cell tumors composed predominantly of embryonal carcinoma. Twenty-seven cases contained adjacent areas of intratubular 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 tumor. In contrast, none of the 17 seminomas and only 2 of 14 embryonal carcinomas 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 corresponding invasive tumor had lost p21 expression. In nine additional cases p21 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 ITGCN. 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 p53-

Hypermethylation of the 5′ CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis

“…An increasing number of tumour suppressor genes have been recognised for which epigenetic silencing is the predominant mechanism of gene inactivation and for which somatic mutations are rare. While several testicular tumour suppressor genes have now been identified (Bartkova et al, 2000;Datta et al, 2001;Luo et al, 2001;Eyzaguirre and Gatalica, 2002;Honorio et al, 2003), only a few, for example RASSF1A (Honorio et al, 2003), MGMT (SmithSorensen et al, 2002), have been reported to be silenced in testicular tumours through DNA hypermethylation.…”

Revisiting DNA damage repair, p53-mediated apoptosis and cisplatin sensitivity in germ cell tumors

“…This is often caused by, overexpression of MDM2, and silencing of the MDM2 regulator ADP Ribosylation Factor (ARF). Because gain of MDM2 expression and ARF mutations are associated with TGCT development (Datta et al, 2001, Iwato et al, 2000, it has been suggested that in TGCTs, MDM2 functional hyperactivation might suppress p53 function (Box A in Fig. 1).…”

Low p21Waf1/Cip1 protein level sensitizes testicular germ cell tumor cells to Fas-mediated apoptosis

“…Furthermore, despite accumulation of p53 only minimal p21 induction occurs in TGCT cells upon chemotherapeutic drug exposure (Chresta et al, 1996;de Jong et al, 1999). In addition, most TGCTs lack p21 protein expression (Guillou et al, 1996;Bartkova et al, 2000;Datta et al, 2001). Several studies have shown that p21 is not only an important mediator of p53-induced cell cycle arrest (El-Deiry et al, 1993 but also of apoptosis suppression following DNA-damaging agents exposure (Gorospe et al, 1997;Gervais et al, 1998;Levkau et al, 1998;Asada et al, 1999;Zhang et al, 1999).…”