[676] Prognosis of Gastric Cancer: A Genome-Wide Study Using 244K Array Comparative Genomic Hybridization (aCGH) and Verification by Fluorescent In-Situ Hybridization (FISH)

CD Truong, A Ylip, W Feng, W Li, T Khoury, J Yao, K Xie, W Zhang, D Tan. The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Accumulated evidence suggests that multiple genetic alterations are involved in the complex carcinogenetic process of solid tumors such as gastric cancer (GC). Although a number of genetic changes has been reported in GC, including amplification of CCNE, CMET, FGFR2 and KSAM, mutation of E-cadherin, KRAS and Tp53 genes, and loss of heterozygosity on 5q, 17p, and 18q, the molecular events leading to GC and its progression remain largely unknown.
Design: Oligonucleotide array comparative genomic hybridization (aCGH) was performed on 40 microdissected GC samples using a high-density (244K) aCGH system (Agilent Technologies). Agilent's Feature Extraction 9531 and aCGH Analytics 3440 software programs were used to map the oligo's signal strength onto a build of the human genome to visualize the gain or loss (based on the reference used in the other channel on the same slide) of DNA. For each aCGH probe, each sample was classified as having normal, gained, or lost DNA copy number based on log 2 ratio thresholds of 0.15. An independent set of tissue arrayed samples (n=63) was further validated by FISH after one focus (19q13.3) was found to have association with patients' survival. The mean patients' survival follow-up time was 58 months.
Results: aCGH identified 1271 genes with DNA copy loss and 1449 genes with DNA copy gain in gastric cancer. Among these identified genes, 1 deleted and 198 amplified genes were observed to have significant association with patients' survival. Forty-eight of these genes were specifically located on chromosome 19q13.3, including CRX, DACT3, DKKL1, EHD2, EMP3, HIF3A, HRC, IGFL2, IGFL3, KPTN, LIG1, PNKP, and PTOV1. Compared with all other patients, those (n=14) with gene amplification on 19q13.3 had a significantly poorer prognosis (p<0.01). Furthermore, using 19q13.3 probe (Vysis, Abbott, IL) by FISH method, amplification of 19q13.3 was identified in 18 cases with unfavorable clinical outcome.
Conclusions: This genome-wide study identified a panel of critical genes associated with progression of gastric cancer. Amplification of the genes on chromosome 19q13.3, a possible signature event in gastric carcinogenesis, represents a potentially useful prognostic biomarker for this aggressive malignancy. Further functional studies are needed to confirm the potential value of these genes in the management of gastric cancer.
Category: Gastrointestinal

Tuesday, March 10, 2009 1:00 PM

Poster Session IV # 106, Tuesday Afternoon