Abstract 4983: Integrative analysis of DNA copy number and gene expression identifies G3BP1 and HIRA as potential therapeutic targets against metastatic oral squamous cell carcinoma

Abstract

Abstract The presence of lymph node metastasis is associated with a 50% reduction of 5-year survival in patients with oral squamous cell carcinoma (OSCC). We set out to combine DNA copy number aberrations (CNAs) with gene expression profiles, to identify CNAs-associated genes dysregulated in metastatic OSCC, and determine whether these genes can be targeted to selectively kill metastatic OSCC tumor cells. Toward this end, we interrogated DNA and RNA of the same OSCC cell populations laser micro-dissected from non-metastatic primary tumors (n=17) and metastatic lymph nodes (n=20) using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR) < 5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Out of these, 114 transcripts showed significant correlation between their DNA copy number alternations (estimated using SNPs within 250 kb upstream and downstream of the transcript) and gene expression (FDR < 0.01). Among these CNA-correlated transcripts, 95 had significantly different DNA copy numbers between metastatic and non-metastatic OSCC (FDR <0.01 by Wilcoxon rank test). These 95 transcripts (representing 87 genes) mainly clustered around three genomic locations: 3p25.3-22.1, 9p24.1- 22.3 and 18q21.1-22.3. Among these 87 genes, we selected 28 of the 58 genes that were over-amplified and over-expressed in metastatic OSCC and conducted a high-throughput siRNA-mediated gene knockdown screen in five cell lines derived from primary and lymph node metastatic OSCC. The expression-knockdown of 18 genes showed 30% or more growth suppression in at least one cell line as compared to mock controls in which the cells were treated with transfection reagent only without the siRNA (P < 0.01). In particular, knocking-down G3BP1 and HIRA selectively suppressed the growth of all OSCC cell lines derived from lymph node metastases when compared to non-metastatic lines. Further investigation is warranted to confirm these findings and to examine the biological role of G3BP1 and HIRA in OSCC metastasis and their potential as therapeutic targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4983. doi:10.1158/1538-7445.AM2011-4983