Comprehensive Molecular Oncogenomic Profiling & microRNA Analysis of Prostate Cancer
Seema Sethi, Dejuan Kong, Greg Dyson, Wael Sakr, Fazlul Sarkar. Wayne State University, Detroit, MI
Background: Comprehensive molecular oncogenomic and microRNA (miRNA) profiling of tumors can provide tumor specific oncogenomic and miRNA signatures which can be useful to improve diagnostic accuracy, refine prognostic and predictive capabilities, and may serve as therapeutic targets. In prostate cancer (PCa) such a comprehensive analysis has not been reported.
Design: DNA and RNA obtained from scant amounts of fresh frozen Pca tumor tissue samples (n=36) were profiled by (1) mutation analysis using Sequenom Massarray & OncoCarta VI panel that profiles 238 common cancer mutations in 19 oncogenes (known predictors of response or resistance to targeted therapies)(2) whole-genome gene expression microarrays & (3) single nucleotide polymorphisms (SNP) microarrays with genome-wide coverage. miRNA analysis was done on RNA from FFPE Pca tumor tissues using RT-PCR. Data was statistically analyzed & correlated with clinical & pathologic variables.
Results: Massarray analysis identified a MET oncogene mutation, variant T992I, in a 49 year old patient with Gleason score 7 (4+3) tumor. Of the 47,224 genes analyzed by gene expression & SNP microarrays, 74 were significant in predicting high tumor grade (p<0.0001) and ILMN_1754102; TGIF1 was the most significant gene. Of 731,442 SNP's analyzed, 1,022 significantly predicted high tumor grade by ordinal regression analysis (p<0.01) and 638 by logistic regression analysis (p<0.01). Ingenuity Pathway analysis revealed the significant genes (p<0.05) were involved in biological pathways for “Gene Expression, Cell Cycle, Cancer”, “Inflammatory Response, Cell Death, Infection Mechanism” and “Cellular Assembly, Organization, Gene Expression, Cancer”. Gene p53 was found to be at the center hub of predicting pathways.
Loss of miR-34a expression was found in PCa tissues consistent with the central role of p53.
Conclusions: Using high throughput genomic profiling & expression analysis of genes & miRNAs, we found that p53 gene is at the center hub of all pathways & loss of miR-34a was consistent with p53 function in PCa. Moreover, MET oncogene mutation is a novel finding, hithereto unreported in PCa & these molecular evidence may have a significant clinical impact on diagnosis, prognosis & in designing targeted therapies to achieve the goal of personalized medicine.
Category: Genitourinary (including renal tumors)
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 121, Monday Morning