IMMUNOHISTOCHEMICAL AND MOLECULAR EVALUATION OF THE MDM-2 GENE-PRODUCT IN BRONCHOGENIC-CARCINOMA

In this study, we investigated immunohistochemically the expression of mdm-2 protein in 93 surgically resected bronchogenic carcinomas. The findings were correlated with p53 protein detection status and clinico pathologic data (histologic type, differentiation grade of the lesions , lymph node metastases, and smoking history of the patients), Thirty of the 93 immunohistochemically examined specimens were subjected to N orthern blot and differential polymerase chain reaction analysis to lo ok into the mechanism of mdm-2 overexpression. Finally, we studied the concordance between p53 immunohistochemical positivity and p53 gene a lterations as assessed by the single-strand conformation polymorphism technique. Seventy-three (78%) and 67 (72%) of 93 carcinomas showed nu clear immunoreactivity for mdm-2 and p53 proteins, respectively. We ob served a high degree of concordance (75%) between p53 mutations and p5 3 immunolabelling, which was even higher in the specimens with p53 pos itivity in more than 50% of the cells (90%). Despite the high percenta ge of mdm-2 and p53 expression, the two molecules were simultaneously detected in 50 (54%) of 93 cases. Forty-two (84%) of the 50 cases were accompanied by p53 mobility shifts, which indicated mutations, Intere stingly, statistical analysis revealed an almost significant correlati on between the carcinomas with mdm-2/p53 coexpression and lymph node d isease (P = 0.058), which indicated a possible ''gain of function'' ph enotype. In addition, absence of reactivity for both proteins was stat istically more frequent in the patients without lymph node disease (P = 0.006). The mdm-2-positive/p53-negative immunohistochemical profile was more often seen in adenocarcinomas (P = 0.003), especially in well -differentiated ones (P = 0.02), than in other histologic types of lun g cancer, which suggested a p53-independent pathway of mdm-2 overexpre ssion. Molecular analysis showed that mdm-2 overexpression was a conse quence of increased transcription rather than of mdm-2 gene amplificat ion. The smoking history of the patients was strongly related to p53 ( P = 10(-4)) even in the group of adenocarcinomas (P = 0.012). No corre lation was observed between cigarette consumption and mdm-2 immunoreac tivity.