Purpose: Chromosomal instability, as assessed by many techniques, including DNA
content aneuploidy, LOH, and comparative genomic hybridization, has consistently been
reported to be common in cancer and rare in normal tissues. Recently, a panel of
chromosome instability biomarkers, including LOH and DNA content, has been reported
to identify patients at high and low risk of progression from Barrett’s esophagus (BE) to
esophageal adenocarcinoma (EA), but required multiple platforms for implementation.
Although chromosomal instability involving amplifications and deletions of chromosome
regions have been observed in nearly all cancers, copy number alterations (CNAs) in premalignant tissues have not been well characterized or evaluated in cohort studies as
biomarkers of cancer risk. Experimental Design: We examined CNAs in 98 patients
having either BE or EA using BAC array CGH to characterize CNAs at different stages
of progression ranging from early BE to advanced EA. Results: CNAs were rare in early
stages (<HGD) but were progressively more frequent and larger in later stages (HGD and
EA), including high level amplifications. The number of CNAs correlated highly with
DNA content aneuploidy. Patients whose biopsies contained CNAs involving more than
70 Mbp were at increased risk of progression to DNA content abnormalities or EA
(HR=4.9, 95% CI 1.6-14.8, p=0.0047), and the risk increased as more of the genome was
affected. Conclusions: Genome wide analysis of CNAs provides a common platform for
evaluation of chromosome instability for cancer risk assessment as well as identification
of common regions of alteration that can be further studied for biomarker discovery
