MDM2 copy number increase: a poor prognostic, molecular event in esophageal squamous cell carcinoma

The present study aimed to elucidate the clinicopathological significance of molecular alterations in MDM2 in esophageal squamous cell carcinoma (ESCC). A total of 399 resected cases of ESCC were examined by dual-color in situ hybridization for MDM2 and immunohistochemistry for p53 using tissue microarrays. Clinicopathological features were correlated with the MDM2 status. Among 362 cases with a successful dual-color in situ hybridization analysis, 19 (5%) and 13 (4%) had MDM2 amplification and chromosome 12 polysomy, respectively, and these were examined as an MDM2-positive group. A comparison between amplified and polysomic cases revealed that the latter were more strongly associated with preoperative chemotherapy than the former. Sixteen (50%) of 32 MDM2-positive cases had positive results in all tissue cores examined, indicating diffuse MDM2 alterations. Cases with the diffuse alteration of MDM2 were characterized by an advanced pT stage and extensive vascular infiltration. The relationship between MDM2 copy number increases and p53 mutations was weak, with the overexpression of p53 being similarly detected in MDM2-positive and MDM2-negative cases (59% versus 49%; P = .267). Overall survival was shorter in patients with MDM2-positive ESCC than in those without MDM2 alterations (P = .033). The poor prognostic value of MDM2 alterations became more obvious when only diffusely altered cases were counted (P = .005). In conclusion, the present study revealed that MDM2 copy number increases occurred in 9% of ESCC cases, and MDM2 alterations, particularly diffuse abnormalities, were associated with a poor prognosis. MDM2-altered ESCC may achieve beneficial effects from MDM2-targeted therapy.