Abstract 5595: Impact of p53 impaired function on outcomes of multiple myeloma patients carrying deleted TP53 and/or amplified MDM4

Abstract

Abstract Background. The TP53 tumor-suppressor gene is mutated or functionally inactivated in most human cancers. In MM, TP53 del on chr 17p13 defines a pts group with a particularly poor prognosis, even if its prevalence at diagnosis is quite low. One of the most potent inhibitor of p53 is MDM4, whose locus is on chr1q32.1, a region frequently amplified in MM. Aim. To investigate the possibility that both TP53 del and MDM4 amp might affect similar pathways, thus finally leading to a poor prognosis MM pts carrying at diagnosis at least one of them. Pts and methods. 89 pts treated with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy prior to, and as consolidation after, double ASCT were analyzed at diagnosis by unpaired analysis CNA (Affymetrix 6.0 SNP array) and GEP (Affymetrix U133 Plus2.0 array); in 21 pts carrying MDM4 amp the p53 activity was explored both by deep sequencing of TP53 (Roche GS Junior 454 platform) and by immunoblotting assays of MDM4, p-p53 and p53. Genomic results were evaluated in the clinical context. Results. CNA analysis showed a 482 Kb minimal del region on chr17p13, including TP53, in 8/89 pts (8,9%) and a 1.1 Mb minimal amp region on chr1q32.1 including MDM4 in 27/89 pts (30,3%). GEP analysis performed in TP53 del and MDM4 amp pts generated two lists, including genes differentially expressed among pts carrying or not either amp MDM4 (4211 probes sets, p<0.05), or del TP53 (2725 genes, p<0.05). In both cases, an overall deregulation of pathways related to the cell cycle, the DNA damage repair and the cell adhesion and cytoskeleton remodeling was shown. In 21 pts carrying MDM4 amp the p53 activity was evaluated by p-p53 immunoblotting assays: the absence of p-p53 protein was shown in 60% of them. The TP53 mutational rate, as detected by deep sequencing of exons 4-11, was analyzed in 21 pts carrying MDM4 amp: point mutations were shown in 15 pts, with mutated reads frequencies ranging from 1.03% to 16.9% (median coverage for each amplicon = 1000 reads). The prognostic relevance of p53 pathway impaired function was evaluated by stratifying pts into two subgroups according to the presence or absence of MDM4 amp and/or TP53 del (group A: 34 pts, 38%, group B; 55 pts, 62%). Baseline clinical characteristics were homogeneous, whereas groups A and B resulted clearly imbalanced with respect to the genomic background: the t(4,14) frequency (38% vs. 14% positive, p=0.0002) and the average number of CNAs (165 vs 103, p = 0.03) were overall higher in group A. Despite the initially slightly higher response rate after VTD (38% vs 20% ≥near complete response), group A pts showed a shorter PFS (40.13 months vs not reached, p=0.001) and OS (66.6 vs not reached, p=0.0006). The poorer impact associated with MDM4 amp was retained also in the absence of TP53 del (PFS: 50.5 months vs not reached, p=0.01). Conclusions. The involvement of the p53 pathway alteration in MM might be wider than expected, possibly due to the activation of negative regulators of p53. Citation Format: Carolina Terragna, Marina Martello, Enrica Borsi, Lucia Pantani, Elena Zamagni, Paola Tacchetti, Annamaria Brioli, Beatrice Anna Zannetti, Flores Dico, Nicoletta Testoni, Giulia Marzocchi, Katia Mancuso, Serena Rocchi, Giovanni Martinelli, Michele Cavo. Impact of p53 impaired function on outcomes of multiple myeloma patients carrying deleted TP53 and/or amplified MDM4. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5595. doi:10.1158/1538-7445.AM2014-5595