p21WAF1/CIP1 AND MDM2 EXPRESSION IN NON-HODGKIN'S LYMPHOMA AND THEIR RELATIONSHIP TO p53 STATUS: A p53+, MDM2−, p21− IMMUNOPHENOTYPE ASSOCIATED WITH MISSENSE p53 MUTATIONS

Abstract

p53 is a tumour suppressor gene which is often found to be inactivated in most types of human cancer. p53 is a transcription factor, the inactivation of which may lead to significant variations in the levels of p53 downstream proteins, such as p21WAF1/CIP1 and MDM2. In view of the significance of p21WAF1/CIP1 and MDM2 as wild‐type (wt) p53 targets, this study was undertaken to monitor the varying expression of these proteins in non‐Hodgkin's lymphomas (NHLs) in relation to p53 gene status. A total of 57 cases of different histological types of NHL were included in this study. Proteins p53, p21and MDM2 were analysed by immunohistochemical techniques, taking the levels expressed in reactive lymphoid tissues as reference points. p53 gene point mutations (exons 5–8) were looked for using the PCR–SSCP technique and direct sequencing. Fifteen of the 57 cases studied showed 16 mutations at the p53 gene: 12 missense, one nonsense, two silent mutations, and one frameshift deletion. Most missense mutations were associated with high levels of p53 protein, while the nonsense mutations and frameshift deletion did not induce detectable levels of p53. All cases with mutation at the p53 gene (15) showed null or low levels of p21WAF1/CIP1 and MDM2 proteins, suggesting that null or missense mutations at this gene give rise to a protein that is unable to transactivate the p21WAF1/CIP1 and MDM2 genes. The association between missense p53 mutation and dissociate immunophenotype (p53+, MDM2−, p21−) was statistically significant (Fisher's exact test, P=0·0024). This anomalous p53+, MDM2−, p21− phenotype was also found in a small group of five cases with wt p53; this could indicate that in these cases p53 transactivation capacity has been abrogated by a mechanism other than p53 mutation. Most cases with the wt p53 gene show simultaneous immunohistochemical expression of all three proteins and often display higher levels than those found in reactive lymphoid tissue. There is a tendency for EBV‐positive cases to harbour high levels of p53+ and p21+, suggesting that EBV could be involved in the nuclear accumulation of p53 and p21WAF1/CIP1 in NHL. © 1997 by John Wiley & Sons, Ltd.

Prognostic impact of P53 status in Ewing sarcoma

“…The demonstration of P53 accumulation in the absence of P21 WAF1 expression correlates well with P53 missense mutations in several studies. [27][28][29] P53 independent induction of P21 WAF1 , however, also has been well described. 30 In our series, all patients that showed P53 expression in Ͼ 20% of cells had no P21 WAF1 expression (6 patients; 11%) ( Fig.…”

Low Expression of p27 Protein Combined with Altered p53 and Rb/p16 Expression Status Is Associated with Increased Expression of Cyclin A and Cyclin B1 in Diffuse Large B-Cell Lymphomas

“…Group 3 is composed of simultaneous detection of low/null p27 expression, increased p53 expression, and decreased Rb or p16 expression (three alterations: 11 cases). lecular networks regulating the cell cycle in malignancies provides valuable information for the understanding of the impaired regulation of these networks and permits further insight into oncogenesis (11,15,17,19,23,24,26,29,34,36). This approach was adopted in the present study to analyze the expression of p27 in relation with components of the p53 and Rb1 growth control pathways and the status of proliferation in 80 cases of DLBCL.…”

Multiple cell cycle regulator alterations in Richter's transformation of chronic lymphocytic leukemia

“…Interestingly, this pattern of p53 and p21 Waf1 expression has also been detected in a remarkable proportion of aggressive NHL. 33,[36][37][38] The presence of a wild-type p53 gene in these p53+/p21+ NHL has led to the idea that p53-induced, p21 Waf1 -mediated growth arrest is overcome by a mechanism of inactivation of the p53 G1 checkpoint pathway acting downstream of p21 Waf1 . 38 A similar inactivating mechanism could take place in some CLL cases and, by conferring a growth advantage to CLL cells, hypothetically cooperate in Richter's transformation.…”

“…Thus, we have now analyzed CDKI p21 Waf1 and p27 Kip2 , Rb and cyclin D1, in a series of CLL and RS tumors well characterized for ARF/INK4a and p53 alterations. 8,19 Although p53 gene abnormalities have been extensively investigated in CLL, [11][12][13][14][15][16] the immunohistochemical pattern of p53/p21 Waf1 expression, a well-established marker of the p53 gene status in NHL, 33,36,37 has not been explored in CLL and RS. 33,38 In the present series, a p53++/p21− immunohistochemical pattern was exclusively shown by p53-mutated tumors.…”