Abstract A14: Chromosomal aberrations predict malignant progression and treatment response of Barrett's-related esophageal neoplasia: A genome-wide high-density SNP array analysis

Abstract

Abstract Chromosomal aberrations occur frequently during malignant progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC). In this study, we applied Illumina's 317K high-density SNP arrays to profile chromosomal aberrations at each of the four sequential stages of progression - Barrett's metaplasia (BM), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC. We observed significant trends of increasing LOH/deletion associated with the degree of progression. The average numbers of chromosome arms with LOH/deletion per sample were 0.30, 3.21, 7.70, and 11.90 for BM, LGD, HGD, and EAC, respectively (p-for trend=4.82×10−7). The mean percentages of SNPs with LOH/deletion events were 0.1%, 1.8%, 6.6%, and 17.2% for BM, LGD, HGD, and EAC, respectively (p-for trend=2.64×10−6). In BM, there were scattered chromosome deletions at 3p14.2 (10%), 16q23.1 (5%), and 9p21 (5%), which became predominant aberrations in LGD. More importantly, the 3p14.2 (68.4%) and 16q23.1 (50%) LOH/deletion in LGD was exclusively limited to narrow regions within the FHIT (3p14.2) and WWOX (16q23.1) genes, the two most frequent common fragile sites in the human genome. In contrast, the 9p21 deletion (68.4%) occurred in larger regions (encompassing p16 gene), often involving the whole 9p arm. A significant increase in LOH/deletion of other chromosomes was seen in HGD and there was widespread LOH/deletion across the whole genome in EAC. 17p (47.6%) LOH was the most frequent event in EAC, which mostly spanned the entire 17p arm with only one focal site of LOH at 17p13.1. There were many recurrent small regions of LOH/deletion that disrupted a single gene, most of which are common fragile sites in the human genome. RUNX1 is a potential tumor suppressor gene in EAC. Amplifications were rarer than LOH/deletions. The average numbers of chromosome arms with amplification per sample were 0.30, 0.42, 1.90, and 8.50 for BM, LGD, HGD, and EAC, respectively (p-for trend=1.35×10−9). The mean percentages of SNPs with amplification were 0.5%, 0.4%, 1.5%, and 8.0% for BM, LGD, HGD, and EAC, respectively (p-for trend=1.26×10−8). The most frequent chromosome amplifications in EAC were 8q24.21 (36.6%, MYC), 8p23.1 (31.7%, CTSB), 7q21 (30.8%, CDK6), 20q13.2 (28.6%, ZNF217), and 7p11.2 (25.6%, EGFR). We then analyzed the associations of chromosomal aberrations with clinical features and pathological response in EAC patients treated with neoadjuvant chemoradiation. The number and size of LOH/deletion were significantly associated with pathological response. Non-responders had a greater number (16.4 vs. 8.5, p=0.060) and larger size (662.2 Mb vs. 290.7 Mb, p=0.034) of LOH/deletions, and higher percentage of aberrant SNPs (25.2% vs. 11.2%, p=0.030) than responders. This study provides a genome-wide catalogue of chromosome aberrations occurring during the malignant progression from BE to EAC with the highest resolution to date. Our data support genetic instability and p16 loss as drivers of early neoplastic progression from metaplasia to dysplasia, and p53 aberrations as late events critical for progression to adenocarcinoma. Chromosomal aberrations can predict malignant progression and treatment response in EAC, which may have important clinical implications for cancer prevention and personalized treatment of EAC. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A14.