The Poor Outcome of Multiple Myeloma (MM) Patients Carrying At Diagnosis Deleted TP53 and or Amplified MDM4 Might Be Related to the Deregulation of Genes Involved in Cell Cycle Control and DNA Damage Repair

The efforts to characterize the genomic background of Multiple Myeloma (MM) and to correctly stratify at diagnosis patients (pts) subsequently treated with novel drugs thoroughly meet the clinical requirement to handle highly powerful prognostic factors. On the other hand, the information obtained from each pts needs to be carefully interpreted, by considering the genomic background as a whole, since each aberration might represent the different expression of a common deregulated pathway. The TP53 deletion on chromosome (chr) 17p13 represents one of the genomic aberration most significantly associated with poor outcome in MM. Overall, the TP53 tumor-suppressor gene inactivation has a central role in the tumorigenesis, since p53 is the most frequently mutated protein in human cancers. The p53 pathway silencing might pass also through changes in the expression level or activation of p53 itself, regulated by several specific inhibitors and/or activators. One of the most potent inhibitor of p53 is MDM4, which is critical for control of p53 activity during response to stress and is often amplified in several types of tumors. The MDM4 locus is located on chr1q32.1, a region frequently amplified in MM.

Since in MM the TP53 deletion on chr 17p13 is reported with low frequencies (7 to 11% at diagnosis) and since the vast majority of hemizygous TP53 deleted pts do not harbor mutations on the allele not affected by the deletion, we sought to investigate the frequency and the prognostic role of TP53 deletion and/or MDM4 amplification in newly diagnosed MM pts, assuming that both of these chromosomal aberrations might contribute to impaired p53 function. All pts have been treated with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy prior to, and as consolidation after, double autologous stem-cell transplantation (ASCT).

Eighty-nine pts treated with VTD incorporated into double ASCT were analyzed at diagnosis by means of unpaired analysis of copy number alterations (CNA) (Affymetrix 6.0 SNP array), gene expression profile (GEP) (Affymetrix U133 Plus2.0 array) and Real-time PCR; the genomic results have been analyzed in the clinical context.

The CNA analysis showed that 9/89 pts (10%) carried a minimal deleted region of 482 Kb on chr17p13.1, including TP53, and that 27/89 pts (30,3%) carried a minimal amplified region of 1.1 Mb on chr1q32.1 including MDM4. Pts were stratified into two subgroups according to the presence of amplified MDM4 and/or deleted TP53 (group A, 34 pts, or 38%) or the absence of both these abnormalities (group B, 55 pts, or 62%). Baseline clinical characteristics were homogeneous, except for a higher rate of IgA isotype in group A. On the contrary, groups A and B were clearly imbalanced with respect to the genomic background: indeed, the t(4,14) frequency, as well as the average number of CNAs were overall higher in group A as compared to group B (38% vs. 14% t(4;14) positive, p=0.0002 and 165 vs 103 CNAs, p = 0.03). A GEP comparison among the two groups of pts highlighted an overall deregulation of pathways related to the cell cycle, the DNA damage repair and the cell adhesion and cytoskeleton remodeling, due to the differentiated expression of 627 probes-set in group A vs group B pts (false discovery rate<0.05). The rate of ³near complete response after VTD induction therapy was 38% in group A, as compared to 20% in group B; the presence of TP53 deletion and/or MDM4 amplification correlated with shorter median TTP (40.13 months vs not reached, p=0.005) and OS (57.6 vs not reached, p=0.02). The poorer impact associated with MDM4 amplification was retained also in the absence of TP53 deletion (TTP: 57.6 months vs not reached, p=0.03). Of note, the MDM4 expression, as detected by Real-time PCR in pts carrying amp1q, even if overall higher as compared to negative pts, showed a wide range of expression, with few pts with very low MDM4 expression level.

We observed that pts carrying amplified MDM4 and/or deleted TP53 showed a significantly higher number of CNAs and the deregulation of genes involved in cell cycle control, as compared to pts lacking these chromosomal aberrations. This might account for the worse outcome of this group of pts. The results overall suggest that the involvement of the p53 pathway alteration in MM might be wider than expected, possibly due to the activation negative regulators of p53.

Cavo:Janssen, Celgene, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.