Moller, MB; Ino, Y; Gerdes, AM; Skjodt, K; Louis, DN; Pedersen, NT
The two gene products of the CDKN2A gene, p16 and p19(ARF),
have recently been linked to each of two major tumour suppressor pathways in human
carcinogenesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylation of the
retinoblastoma gene product by cyclin D-dependent kinases, whereas p19(ARF) targets MDM2, a p53
inhibitory protein, for degradation. A deletion of CDKN2A would therefore disturb both pathways.
To explore the p53 pathway genes as a functional unit in diffuse large B cell non-Hodgkin's
lymphomas (DLCL), we wanted to see whether there exists mutually exclusiveness of aberrations of
CDKN2A, MDM2 and p53, since this has not been analysed previously. We investigated 37 DLCL for
aberrations of p15, p16, p19(ARF), MDM2, and p53 at the epigenetic, genetic and/or protein
levers. Homozygous deletion of CDKN2A was detected in seven (19%) of 37 tumours, and another
three cases were hypermethylated at the 5' CpG island of p16. No point mutations were found in
CDKN2B or CDKN2A. immunohistochemical staining of formalin-fixed, paraffin-embedded tissue for
p16 confirmed these results, as all tumours with alterations of CDKN2A were pie immunonegative.
We found p53 mutations in eight (22%) cases and MDM2 overexpression in 16 (43%) tumours. Twenty-
three (62%) tumours had alterations of one or more p53 pathway components (p53, p19(ARF) and
MDM2). Furthermore, 7/9 (78%) p16-immunonegative tumours showed co-aberration of p53 and/or MDM2.
The lack of correlation between these aberrations suggests that DLCL acquire additional growth
advantage by inactivating both of these critical regulatory pathways.