Genome-Wide Copy Number Analysis in Esophageal Adenocarcinoma Using High-Density Single-Nucleotide Polymorphism Arrays

Abstract

We applied whole-genome single-nucleotide polymorphism arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range, 23-208) per tumor. LOH and gains averaged 33 (range, 3-83) and 31 (range, 11-73) per tumor, respectively. Copy neutral LOH events averaged 27 (range, 7-57) per EAC. We noted 126 homozygous deletions (HD) across the EAC panel (range, 0-11 in individual tumors). Frequent HDs within FHIT (17 of 23), WWOX (8 of 23), and DMD (6 of 23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSG), including CDKN2A, CDKN2B, SMAD4, and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 may be targeted. Frequent gains were noted around MYC (13 of 23), BCL9 (12 of 23), CTAGE1 (14 of 23), and ZNF217 (12 of 23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53, and MYC in EAC and identified additional genes of interest. Meta-analysis of previous genome-wide EAC studies together with the data presented here highlighted consistent regions of gain on 8q, 18q, and 20q and multiple LOH regions on 4q, 5q, 17p, and 18q, suggesting that more than one gene may be targeted on each of these chromosome arms. The focal gains and deletions documented here are a step toward identifying the key genes involved in EAC development.

Early Diagnostic Biomarkers for Esophageal Adenocarcinoma—The Current State of Play

“…(177) (195) (Continued on the following page) decade, several studies conducted using advanced genomic techniques such as array-comparative genomic hybridization (aCGH) and SNP arrays confirmed previously reported copy number alterations and identified novel genomic loci undergoing changes during process of metaplasia-dysplasia-carcinoma development (54)(55)(56)(57)(58)(59)(60). It has been shown that as the disease progresses from early to late stages, SNP abnormalities increase from approximately 2% to 30% (54,57).…”

“…It has been shown that as the disease progresses from early to late stages, SNP abnormalities increase from approximately 2% to 30% (54,57). The total number of SNP alterations in tissue samples is tightly correlated with previously reported DNA abnormalities such as aneuploidy, copy number alterations, and LOH highlighting the application of SNP-based genotyping to assess genomic abnormalities (54)(55)(56)(57)(58)(59)(60). Thus, SNP-based genotyping provides an alternative way to assess genomic abnormalities during EAC pathogenesis.…”

Integrative analysis of array-comparative genomic hybridisation and matched gene expression profiling data reveals novel genes with prognostic significance in oesophageal adenocarcinoma

“…Copy number information was obtained from the dataset by Nancarrow et al 14 (GEO accession number GSE 10506). This is the only aCGH dataset currently publicly available with patient survival information.…”

DNA methylation profiling in Barrett’s esophagus and esophageal adenocarcinoma reveals unique methylation signatures and molecular subclasses

“…[9][10][11][12] There is considerable evidence that chromosomal instability plays a role in the progression of BE to EAC, including both gains and losses of whole chromosomes or parts of chromosomes. [13][14][15] Molecular studies of BE epithelia led to the discovery that 9p LOH and CDKN2A negative. CIMP status has been shown to correlate with particular genetic mutations (e.g., CIMP-high cancers with BRAF mutations) as well as clinical parameters (e.g., CIMP-high cancers are more common in female patients and are frequently located in the right colon).…”