Genetic mechanisms of TP53 loss of heterozygosity in Barrett's esophagus: Implications for biomarker validation

V. Jon Wongsurawat, Jennifer C. Finley, Patricia C. Galipeau, Carissa A. Sanchez, Carlo C. Maley, Xiaohong Li, Patricia L. Blount, Robert D. Odze, Peter S. Rabinovitch, Brian J. Reid

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Background and Aims: 17p (TP53) loss of heterozygosity (LOH) has been reported to be predictive of progression from Barrett's esophagus to esophageal adenocarcinoma, but the mechanism by which TP53 LOH develops is unknown. It could be (a) DNA deletion, (b) LOH without copy number change, or (c) tetraploidy followed by genetic loss. If an alternative biomarker assay, such as fluorescence in situ hybridization (FISH), provided equivalent results, then translation to the clinic might be accelerated, because LOH genotyping is presently limited to research centers. Methods: We evaluated mechanisms of TP53 LOH to determine if FISH and TP53 LOH provided equivalent results on the same flow-sorted samples (n = 43) representing established stages of clonal progression (diploid, diploid with TP53 LOH, aneuploid) in 19 esophagectomy specimens. Results: LOH developed by all three mechanisms: 32% had DNA deletions, 32% had no copy number change, and 37% had FISH patterns consistent with a tetraploid intermediate followed by genetic loss. Thus, FISH and LOH are not equivalent (P < 0.000001). Conclusions: LOH develops by multiple chromosome mechanisms in Barrett's esophagus, all of which can be detected by genotyping. FISH cannot detect LOH without copy number change, and dual-probe FISH is required to detect the complex genetic changes associated with a tetraploid intermediate. Alternative biomarker assay development should be guided by appreciation and evaluation of the biological mechanisms generating the biomarker abnormality to detect potential sources of discordance. FISH will require validation in adequately powered longitudinal studies before implementation as a clinical diagnostic for esophageal adenocarcinoma risk prediction.

Original languageEnglish (US)
Pages (from-to)509-516
Number of pages8
JournalCancer Epidemiology Biomarkers and Prevention
Volume15
Issue number3
DOIs
StatePublished - Mar 2006

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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