Abstract 2841: A SNP in the 3'-UTR of the MDMX gene is strongly correlated with decreased overall and disease-free survival in ovarian carcinoma patients in an estrogen-receptor-dependent manner

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The tumor suppressor p53 is inactivated in the vast majority of cancers, either by mutations of the p53 gene itself or by alterations of p53-regulating factors. The MDM2 homologue, MDMX, is another critical negative regulator of p53. Only a few data exist so far, demonstrating the clinical importance of SNPs in the MDMX gene. The aim of our study was therefore to perform sequencing analyses to identify mutations and/or SNPs in the MDMX gene. A single nucleotide polymorphism (A/C) was identified in the 3′-UTR, 31 bp downstream of the stop codon ([SNP34091][1]; rs4245739). In high-grade carcinomas, we found the SNP at a relatively high frequency in the wild-type (A/A) state (62.5%) and in 36% in the heterozygous (A/C) state compared with low-grade carcinomas (45.5%, 45.5%, respectively). The A-allele was associated with increased expression of the full-length MDMX-mRNA. Furthermore, tumors of females who were homozygous for the A-allele showed an increased expression of the MDMX protein. By Cox-regression analysis we found that in estrogen receptor negative tumors the A-allele of [SNP34091][1] was strongly associated with an increased risk of recurrence (RR=8.2; p=0.009) and decreased overall survival time (RR=6.7; p=0.014). According to miRNA-databases the [SNP34091][1] of the MDMX gene is a potential target of miR-191 if the C-allele is present. Therefore, we subsequently analyzed the impact of miR-191 on MDMX expression. We found that mimics of miR-191 resulted in a significantly decrease of MDMX protein levels in C/C ovarian carcinoma cells (Efo-21) but not in cells homozygous for the A-allele (OAW-42). Since MDMX-mRNA levels remained unchanged after transfection, we suggest that miR-191 blocks translation of the MDMX-mRNA and does not lead to its destabilization. These data show that the A-allele increases translation of the MDMX-mRNA which in turn results in a weakened p53-tumor suppressor pathway. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2841. [1]: /lookup/external-ref?link_type=GENPEPT&access_num=SNP34091&atom=%2Fcanres%2F70%2F8_Supplement%2F2841.atom