1. MDM2 amplification is an independent prognostic feature of node-negative, estrogen receptor-positive early-stage breast cancer
Matthias Choschzick, Uwe Heilenkötter, Annette Lebeau, Fritz Jaenicke, Luigi Terracciano, Carsten Bokemeyer, Guido Sauter, Ronald Simon Cancer Biomark. 2010;8(2):53-60. doi: 10.3233/DMA-2011-0806.
Background: MDM2 is overexpressed and amplified in a number of malignant tumors including breast carcinomas. Cell culture experiments showed a close connection between %of MDM2 expression and estrogen receptor status in breast cancer cell lines. Only little is known about the role of MDM2 amplifications in early-stage breast carcinomas with positive estrogen receptor status. Methods: 661 highly characterized node-negative breast carcinomas with positive estrogen receptor status (ER+ early-stage breast carcinomas) were analyzed on a tissue microarray. Molecular (HER2, CCND1, MDM2, MYC, 8q21), as well as estrogen receptor expression data used in this analysis, was available from previously published studies. The primary endpoint of overall survival analysis was death after 10 years. Results: Gene amplifications were found in 194/661 (29%) ER+ early-stage breast carcinomas and 40 (7%) exhibited amplification of the MDM2 oncogene. MDM2 amplifications were significantly related to advanced tumor stage (p < 0.05) and high Ki67 expression levels (p < 0.05). There was no relationship between MDM2 copy number changes and tumor grade, estrogen receptor expression level and co-amplification of HER2, CCND1 and 8q. Tumor stage (pT1 vs pT2-pT4; HR 1.51; 95% CI 1.02-2.24; p=0.042), grading (G1-G2 vs G3; HR 2.27; 95% CI 1.51-3.43; p < 0.001), high Ki67 proliferation index (HR 2.03; 95% CI 1.31-3.15; p=0.0015), HER2 (HR 2.6; 95% CI 1.51 to 4.5; p < 0.001) and MDM2 amplification (HR 2.05, 95% CI 1.06-3.97, p =0.033) were statistically adverse prognostic risk factors in univariate Cox regression analysis. Patient age, estrogen receptor expression level, CCND1 and 8q amplification were not associated to overall survival. Multivariate Cox regression analysis of survival data included tumor stage, grading, Ki67 labeling index, HER2 and MDM2 amplification status. In this statistical model, only MDM2 amplification was an independent factor for overall patient survival in ER+ early- stage breast carcinomas (HR 2.64; 95% CI 1.32 to 5.28; p=0.006). Conclusion: The MDM2 oncogene is amplified in a substantial proportion of ER+ early-stage breast carcinomas and an independent parameter for poor patient outcome in this subgroup. The prognostic effect of MDM2 is closely connected to estrogen receptor expression of breast carcinomas.
2. Relationship between HPV16/18 E6 and 53, 21WAF1, MDM2, Ki67 and cyclin D1 expression in esophageal squamous cell carcinoma: comparative study by using tissue microarray technology
Z L Qi, X Huo, X J Xu, B Zhang, M G Du, H W Yang, L K Zheng, J Li, Z Y Shen Exp Oncol. 2006 Sep;28(3):235-40.
Aim: To investigate the role of human papillomavirus (HPV) HPV16/18 E6 oncogene in the carcinogenesis of esophageal cell carcinoma (ESCC). Materials and methods: Tissue microarray (TMA) block was constructed from 60 cases of paraffin-embedded ESCC tissues and pair-matched controls (adjacent normal epithelium). Immunohistochemistry (IHC) methods were applied to detect the expression of HPV16/18 E6, p53, p21(WAF1), MDM2, Ki67 and cyclin D1 proteins on TMA slides. In situ hybridization (ISH) targeting HPV gene was also used. Results: In ESCC samples, 18.3% (11/60) were revealed HPV16/18 E6 positive by IHC, while 40.0% (24/60) HPV positive by ISH; HPV16/18 E6 expression was significantly higher than that of control samples. In ESCC samples, the expressions of p53, p21(WAF1), Cyclin D1, MDM2 and Ki67 were recorded in 60.0% (36/60), 40.0% (24/60), 51.7% (31/60), 65.0% (39/60) and 88.3% (53/60) cases respectively, In ESCC samples, p53, MDM2 and Ki67 expression correlated with the HPV16/18 E6 expression (p less, similar 0.01), p21(WAF1) expression - with these of MDM2 and cyclin D1 (p less, similar 0.01) whilst expression of Ki67 - with ESCC grade (p less, similar 0.01). Conclusion: HPV might be one of etiological factor of esophageal carcinoma in Shantou, China. p53, MDM2 proteins may play important roles in the pathogenesis of HPV-associated ESCC.
