Impact Of p53 Impaired Function On Outcomes Of Multiple Myeloma Patients Carrying Deleted TP53 and/Or Amplified MDM4

• Published in: Blood 2013-11, Vol.122 (21), p.1855-1855
• Main Authors: Terragna, Carolina, Martello, Marina, Borsi, Enrica, Pantani, Lucia, Zamagni, Elena, Tacchetti, Paola, Annamaria, Brioli, Zannetti, Beatrice Anna, Dico, Flores, Testoni, Nicoletta, Marzocchi, Giulia, Mancuso, Katia, Rocchi, Serena, Martinelli, Giovanni, Cavo, Michele
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V122.21.1855.1855

Multiple Myeloma (MM) is a genetically complex disease. In MM, prevalent chromosomal numerical and structural aberrations are used to cluster patients (pts) into subtypes, frequently displaying distinct clinical behaviors. Among the umpteen chromosomal aberrations described so far in MM, the TP53 deletion on chromosome (chr) 17p13 defines a pts group with a particularly poor prognosis, even if its prevalence at diagnosis is quite low. Overall, the TP53 tumor-suppressor gene is mutated or functionally inactivated in most human cancers. Tumors that retain wild-type p53 frequently harbor defects either in the pathways that allow for p53 stabilization in response to stress, or in the effectors of p53 apoptotic activity. One of the most potent inhibitor of p53 is MDM4, which is often amplified in several types of tumors. The MDM4 locus is located on chr1q32.1, a region frequently amplified in MM. Aim of the present work was to investigate the possibility that both TP53 deletion (del) and MDM4 amplification (amp) might affect similar pathways, thus finally leading to a poor prognosis MM pts carrying at diagnosis at least one of them. Eighty-nine pts treated with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy prior to, and as consolidation after, double ASCT were analyzed at diagnosis by means of unpaired analysis of copy number alterations (CNA) (Affymetrix 6.0 SNP array) and gene expression profile (GEP) (Affymetrix U133 Plus2.0 array); in twenty-one pts carrying MDM4 amplification and for whom samples were available, the p53 activity was explored both by analyzing the TP53 mutational rate by deep sequencing (Roche GS Junior 454) and by evaluating the p53 activity by immunoblotting assays of MDM4, p-p53 and p53. Genomic results were evaluated in the clinical context. The CNA analysis showed a 482 Kb minimal deleted region on chr17p13, including TP53, in 8/89 pts (8,9%) and a 1.1 Mb minimal amplified region on chr1q32.1 including MDM4 in 27/89 pts (30,3%). The GEP analysis performed at diagnosis in TP53 del and MDM4 amp pts generated two lists, including genes either differentially expressed among pts carrying or not amplified MDM4 (5840 probes sets, corresponding to 3841 genes, p