Chromosomal instability and copy number alterations in Barrett's esophagus and esophageal adenocarcinoma.
OBJECTIVE
Chromosomal instability, as assessed by many techniques, including DNA content aneuploidy, loss of heterozygosity, 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 loss of heterozygosity 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 (CNA) in premalignant tissues have not been well characterized or evaluated in cohort studies as biomarkers of cancer risk.


METHODS
We examined CNAs in 98 patients having either BE or EA using Bacterial Artificial Chromosome (BAC) array comparative genomic hybridization to characterize CNAs at different stages of progression ranging from early BE to advanced EA.


RESULTS
CNAs were rare in early stages (less than high-grade dysplasia) but were progressively more frequent and larger in later stages (high-grade dysplasia and EA), including high-level amplifications. The number of CNAs correlated highly with DNA content aneuploidy. Patients whose biopsies contained CNAs involving >70 Mbp were at increased risk of progression to DNA content abnormalities or EA (hazards ratio, 4.9; 95% confidence interval, 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 the evaluation of chromosome instability for cancer risk assessment as well as for the identification of common regions of alteration that can be further studied for biomarker discovery.
Paulson
Thomas G
TG
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. tpaulson@fhcrc.org
Maley
Carlo C
CC
Li
Xiaohong
X
Li
Hongzhe
H
Sanchez
Carissa A
CA
Chao
Dennis L
DL
Odze
Robert D
RD
Vaughan
Thomas L
TL
Blount
Patricia L
PL
Reid
Brian J
BJ
D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization / Q000379:methods; D004273:DNA, Neoplasm / Q000378:metabolism; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005434:Flow Cytometry; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009367:Neoplasm Staging
D004273:DNA, Neoplasm