Publication date: Available online 18 April 2019
Source: Human Pathology
Author(s): Ryuichiro Sawada, Ritsuko Maehara, Taro Oshikiri, Tetsu Nakamura, Tomoo Itoh, Yuzo Kodama, Yoshihiro Kakeji, Yoh Zen
Summary
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 (DISH) for MDM2 and immunohistochemistry for p53 using tissue microarrays. Clinicopathological features were correlated with the MDM2 status. Among 362 cases with a successful DISH 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 pre-operative chemotherapy than the former. Sixteen out of 32 (50%) 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% vs. 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.
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