Deletion at fragile sites is a common and early event in Barrett's esophagus

Lisa A. Lai, Rumen Kostadinov, Michael T. Barrett, Daniel A. Peiffer, Dimitry Pokholok, Robert Odze, Carissa A. Sanchez, Carlo Maley, Brian J. Reid, Kevin L. Gunderson, Peter S. Rabinovitch

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1084-1094
Number of pages11
JournalMolecular Cancer Research
Volume8
Issue number8
DOIs
StatePublished - Aug 2010
Externally publishedYes

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Barrett Esophagus
Proto-Oncogene Proteins c-fos
Loss of Heterozygosity
Biomarkers
DNA Breaks
Genomic Instability
Tumor Biomarkers
Bile Acids and Salts
Adenocarcinoma
Genome
Inflammation
Polymerase Chain Reaction
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Lai, L. A., Kostadinov, R., Barrett, M. T., Peiffer, D. A., Pokholok, D., Odze, R., ... Rabinovitch, P. S. (2010). Deletion at fragile sites is a common and early event in Barrett's esophagus. Molecular Cancer Research, 8(8), 1084-1094. https://doi.org/10.1158/1541-7786.MCR-09-0529

Deletion at fragile sites is a common and early event in Barrett's esophagus. / Lai, Lisa A.; Kostadinov, Rumen; Barrett, Michael T.; Peiffer, Daniel A.; Pokholok, Dimitry; Odze, Robert; Sanchez, Carissa A.; Maley, Carlo; Reid, Brian J.; Gunderson, Kevin L.; Rabinovitch, Peter S.

In: Molecular Cancer Research, Vol. 8, No. 8, 08.2010, p. 1084-1094.

Research output: Contribution to journalArticle

Lai, LA, Kostadinov, R, Barrett, MT, Peiffer, DA, Pokholok, D, Odze, R, Sanchez, CA, Maley, C, Reid, BJ, Gunderson, KL & Rabinovitch, PS 2010, 'Deletion at fragile sites is a common and early event in Barrett's esophagus', Molecular Cancer Research, vol. 8, no. 8, pp. 1084-1094. https://doi.org/10.1158/1541-7786.MCR-09-0529
Lai LA, Kostadinov R, Barrett MT, Peiffer DA, Pokholok D, Odze R et al. Deletion at fragile sites is a common and early event in Barrett's esophagus. Molecular Cancer Research. 2010 Aug;8(8):1084-1094. https://doi.org/10.1158/1541-7786.MCR-09-0529
Lai, Lisa A. ; Kostadinov, Rumen ; Barrett, Michael T. ; Peiffer, Daniel A. ; Pokholok, Dimitry ; Odze, Robert ; Sanchez, Carissa A. ; Maley, Carlo ; Reid, Brian J. ; Gunderson, Kevin L. ; Rabinovitch, Peter S. / Deletion at fragile sites is a common and early event in Barrett's esophagus. In: Molecular Cancer Research. 2010 ; Vol. 8, No. 8. pp. 1084-1094.
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abstract = "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.",
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AU - Odze, Robert

AU - Sanchez, Carissa A.

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