MiR-182 and Its Target Gene Dysregulation in Ovarian Carcinoma: Pathology and Clinical Analysis
Brian D McMillen, Zhaojian Liu, Magarita Aponte, Irene Helenowski, Denise Scholtens, Barbara Buttin, Jian-Jun Wei. Northwestern University, Chicago, IL
Background: BRCA1/BRCA2 mutations are hallmarks of high grade papillary serous carcinoma (H-PSC). Nearly 50% of H-PSC shows genomic alterations of BRCA1/BRCA2. If inactivation of BRCA1/2 is critical in the early tumorigenesis of H-PSC, interference with BRCA1/2 expression by non-genomic mechanisms may exist. We and other investigators have demonstrated that several H-PSC associated genes, including BRCA1, HMGA2, FOXO3 and MTSS1 are directly regulated by miR-182. Presently, we intend to investigate the expression of miR-182 and its target genes in a cohort of advanced ovarian cancer patients.
Design: We aimed to examine whether miR-182 and its target gene expression are associated with H-PSC histology and outcome. 117 cases with advanced ovarian cancer (88 H-PSC, 29 non-serous carcinoma) and 30 normal fallopian tubes were obtained from patients treated at Northwestern University between 2002 and 2007. Tissue microarrays in duplicate were prepared and stained for miR-182 and BRCA1, HMGA2, FOXO3 and MTSS1. Gene expression patterns in association with pathology andclinical outcomes were analyzed by various statistical modalities.
Results: H-PSC demonstrated significantly higher miR-182 (p = 0.002) and HMGA2 (p = 0.02) expression, and significantly lower BRCA (p=0.052) and FOXO3 (p<0.0001) expression than normal fallopian tube tissue. miR-182 is significantly correlated with MTSS1 expression (r=0.31; p < 0.001), while other target genes did not show a significant correlation with miR-182. These findings suggest complicated regulation mechanisms between the genes involved in H-PSC. Among examined miR-182 target genes, only HMGA2 was significantly associated with serous type carcinomas (p<0.01), ascites (p<0.009) and decreased overall survival (p=0.02) (Figure 1). FOXO3 expression was associated with lower stage of disease (p = 0.04) and a solid histologic growth pattern (p=0.03).
Conclusions: miR-182 is significantly overexpressed in most H-PSC. The level of BRCA1 expression has no significant correlation with histological features and clinical outcome. In contrast, HMGA2 is significantly associated with H-PSC and worse clinical outcome.
Category: Gynecologic & Obstetrics
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 206, Wednesday Afternoon