Deletion at fragile sites is a common and early event in Barrett's esophagus.
Barrett's esophagus (BE) is a premalignant intermediate to esophageal adenocarcinoma, which develops in the context of chronic inflammation and exposure to bile and acid. We asked whether there might be common genomic alterations that could be identified as potential clinical biomarker(s) for BE by whole genome profiling. We detected copy number alterations and/or loss of heterozygosity at 56 fragile sites in 20 patients with premalignant BE. Chromosomal fragile sites are particularly sensitive to DNA breaks and are frequent sites of rearrangement or loss in many human cancers. Seventy-eight percent of all genomic alterations detected by array-CGH were associated with fragile sites. Copy number losses in early BE were observed at particularly high frequency at FRA3B (81%), FRA9A/C (71.4%), FRA5E (52.4%), and FRA 4D (52.4%), and at lower frequencies in other fragile sites, including FRA1K (42.9%), FRAXC (42.9%), FRA 12B (33.3%), and FRA16D (33.3%). Due to the consistency of the region of copy number loss, we were able to verify these results by quantitative PCR, which detected the loss of FRA3B and FRA16D, in 83% and 40% of early molecular stage BE patients, respectively. Loss of heterozygosity in these cases was confirmed through pyrosequencing at FRA3B and FRA16D (75% and 70%, respectively). Deletion and genomic instability at FRA3B and other fragile sites could thus be a biomarker of genetic damage in BE patients and a potential biomarker of cancer risk.
Lai
Lisa A
LA
Department of Pathology,University of Washington, Seattle, WA, USA.
Kostadinov
Rumen
R
Barrett
Michael T
MT
Peiffer
Daniel A
DA
Pokholok
Dimitry
D
Odze
Robert
R
Sanchez
Carissa A
CA
Maley
Carlo C
CC
Reid
Brian J
BJ
Gunderson
Kevin L
KL
Rabinovitch
Peter S
PS
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D043283:Chromosome Fragile Sites / Q000235:genetics*; D002873:Chromosome Fragility; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D018628:Gene Dosage; D020869:Gene Expression Profiling; D042822:Genomic Instability; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009363:Neoplasm Proteins; D012333:RNA, Messenger