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

¹ Oncogenomics and ² Cancer and Population Studies, Queensland Institute of Medical Research, Herston, Queensland, Australia; ³ Upper Gastrointestinal and Soft Tissue Unit, Princess Alexandra Hospital, and Department of Surgery, University of Queensland, Princess Alexandra Hospital; ⁴ School of Medicine, Southern Clinical Division, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia; ⁵ Department of Surgery, University of Adelaide, Royal Adelaide Hospital, Adelaide, South Australia, Australia; and ⁶ School of Nursing and Midwifery and ⁷ Department of Surgery, Flinders University, Bedford Park, South Australia, Australia

Requests for reprints: Derek J. Nancarrow, Oncogenomics, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4029, Australia. Phone: 61-7-33620323; Fax: 61-7-38453508; E-mail: derek.nancarrow{at}qimr.edu.au.

Key Words: esophageal adenocarcinoma • array comparative genomic hybridization • loss of heterozygosity • DNA copy number • amplification • homozygous deletion

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. [Cancer Res 2008;68(11):4163–72]

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