Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Abstract

BACKGROUND: Relatively few sarcomas harbor TP53 (tumor protein p53) mutations, but in many cases, amplification of MDM2 (murine double minute 2) effectively inactivate p53. The p53 pathway activity can also be affected by normal genetic variation. METHODS: The mutation status of TP53 and expression of MDM2, TP53, and their genetic variants SNP309 and R72P (Arg72Pro) were investigated in 125 sarcoma patient samples and 18 sarcoma cell lines. Association of the different genotypes and gene aberrations with chemotherapy response and survival, as well as response to MDM2 antagonists in vitro was evaluated. RESULTS: Twenty-two percent of the tumors had mutant TP53 and 20% MDM2 gene amplification. Patients with wild-type TP53 (TP53 Wt ) tumors had improved survival (P < .001) and TP53 Wt was an independent prognostic factor (hazard ratio ¼ 0.41; 95% confidence interval ¼ 0.23-0.74; P ¼ .03). Interestingly, there was a trend toward longer time to progression after chemotherapy for tumors with the apoptosis-prone p53 variant R72 (P ¼ .07), which was strongest with doxorubicin/ifosfamide-based regimens (P ¼ .01). Liposarcomas had low R72 frequency (33% versus 56%), but increased levels of MDM2 and MDM4 (51% and 11%, P < .001). MDM2 overexpression on a TP53 Wt background predicted better response to MDM2 antagonist Nutlin-3a, irrespective of R72P or SNP309 status. CONCLUSIONS: Improved survival after chemotherapy was found in patients with TP53 Wt tumors harboring the R72 variant. MDM2 overexpression in TP53 Wt tumors predicted good response to MDM2 antagonists, irrespective of R72P or SNP309 status. Thus, detailed TP53 and MDM2 genotype analyses prior to

The Roles of MDM2 and MDMX in Cancer

“…In gastric cancer, high expression of MDM2 correlated with shorter overall survival time without adjuvant treatment, but following treatment with fluorouracil–leucovorin–oxaliplatin, high expression of MDM2 correlated with higher overall survival (164). Increased MDM2 and MDMX levels in liposarcomas have been shown to correlate with enhanced sensitivity to Nutlin 3a, a well-studied molecule that disrupts the p53–MDM2 interaction in vivo (165). This underscores the importance of MDM2 and MDMX as biomarkers in human cancer and as predictors of therapeutic response.…”

Genetic Variants of the MDM2 Gene Are Predictive of Treatment-Related Toxicities and Overall Survival in Patients With Advanced NSCLC

“…The association between the functional SNP T309G (rs2279744) and platinum-based or noneplatinum-based chemotherapy responses has been investigated in many cancers. 18,35,[40][41][42][43] However, the results have been inconsistent regarding the effects of this SNP on gastrointestinal and hematologic toxicities. No significant effects were found in 136 patients with bladder cancer who received combined cisplatinbased systemic chemotherapy and radiotherapy.…”

Mdm2 and p53 Expression in Radiation-Induced Sarcomas of the Head and Neck: Comparison with &lt;i&gt;De Novo&lt;/i&gt; Sarcomas

“…The Mdm2-p53 interaction in sarcomas has recently received attention on account of a new therapeutic approach targeting this interaction[10,11,16]. MDM2 amplification/overexpression is characteristic of well-differentiated/dedifferentiated liposarcomas (DDLS), but is also identified in a small percentage of other sarcomas[17,18].…”

“…The poor prognosis and therapeutic difficulties of RISs have been described by many researchers[5-9]. Recently, Mdm2 inhibitors have emerged as novel therapeutic agents for some sarcomas[10,11]. Immunohistochemical examinations of Mdm2 expression in RIS have not been published to date.…”