Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma

The two gene products of the CDKN2A gene, p16 and p19(ARF), have recently b een linked to each of two major tumour suppressor pathways in human carcino genesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylat ion of the retinoblastoma gene product by cyclin D-dependent kinases, where as p19(ARF) targets MDM2, a p53 inhibitory protein, for degradation. A dele tion of CDKN2A would therefore disturb both pathways. To explore the p53 pa thway genes as a functional unit in diffuse large B cell non-Hodgkin's lymp homas (DLCL), we wanted to see whether there exists mutually exclusiveness of aberrations of CDKN2A, MDM2 and p53, since this has not been analysed pr eviously. We investigated 37 DLCL for aberrations of p15, p16, p19(ARF), MD M2, and p53 at the epigenetic, genetic and/or protein levers. Homozygous de letion of CDKN2A was detected in seven (19%) of 37 tumours, and another thr ee cases were hypermethylated at the 5' CpG island of p16. No point mutatio ns were found in CDKN2B or CDKN2A. immunohistochemical staining of formalin -fixed, paraffin-embedded tissue for p16 confirmed these results, as all tu mours with alterations of CDKN2A were pie immunonegative. We found p53 muta tions in eight (22%) cases and MDM2 overexpression in 16 (43%) tumours. Twe nty-three (62%) tumours had alterations of one or more p53 pathway componen ts (p53, p19(ARF) and MDM2). Furthermore, 7/9 (78%) p16-immunonegative tumo urs showed co-aberration of p53 and/or MDM2. The lack of correlation betwee n these aberrations suggests that DLCL acquire additional growth advantage by inactivating both of these critical regulatory pathways.