Amplification of the Genes on Chromosome 19q13.3 Represents the Signature Molecular Event Predicting the Clinical Outcome of Gastric Adenocarcinoma
Dongfeng Tan, Thaer Khour. MD Anderson Cancer Center, Houston, TX
Background: A handful evidence suggests that multiple genetic alterations are involved in the complex carcinogenetic process of gastric adenocarcinoma (GAC). Although a number of genetic changes have been reported in GAC, including amplification of c-MET and FGFR2, and mutations of CDH1 and KRAS, the molecular events leading to GAC and its progression remain largely unknown. To assess global molecular changes in GAC, we use high thorough-put whole genomic assay to evaluate human GAC samples.
Design: Oligonucleotide array comparative genomic hybridization (aCGH) was performed on 48 GAC samples using a high-density (244K) aCGH method (Agilent Technologies). 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=77) was further validated by fluorescent in-situ hybridization (FISH) by using probes visualizing 19q13.3 (red signal) and the centromere (green signal). Amplification of 19q13.3 was defined if the ratio of 19q13.3 to centromere is greater than 2.2. The mean patient's survival follow-up time was 76 months.
Results: aCGH identified 1271 genes with DNA copy loss and 1449 genes with DNA copy gain in gastric cancer. Among these identified genes, 11 deleted and 198 amplified genes were observed to have significant association with patient's survival. Forty-eight of amplified 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=16) with gene amplification on 19q13.3 had a significantly poorer prognosis (p<0.01), independent of other conventional prognosis factors including TNM stage. These results were further confirmed by FISH method and amplification of 19q13.3 was identified in 20 cases with unfavorable clinical outcome.
Conclusions: This genome-wide study identified a panel of critical genes associated with progression of GAC. 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. Relevant functional studies are to be confirmed the potential value of these genes in the management of gastric cancer.
Wednesday, March 6, 2013 1:00 PM
Poster Session VI # 93, Wednesday Afternoon