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 Maley, Xiaohong Li, Patricia L. Blount, Robert D. Odze, Peter S. Rabinovitch, Brian J. Reid

Research output: Contribution to journalArticle

36 Citations (Scopus)

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
Externally publishedYes

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Barrett Esophagus
Loss of Heterozygosity
Biomarkers
Fluorescence In Situ Hybridization
Tetraploidy
Diploidy
Adenocarcinoma
Esophagectomy
DNA
Aneuploidy
Longitudinal Studies
Chromosomes

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Genetic mechanisms of TP53 loss of heterozygosity in Barrett's esophagus : Implications for biomarker validation. / Wongsurawat, V. Jon; Finley, Jennifer C.; Galipeau, Patricia C.; Sanchez, Carissa A.; Maley, Carlo; Li, Xiaohong; Blount, Patricia L.; Odze, Robert D.; Rabinovitch, Peter S.; Reid, Brian J.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 15, No. 3, 03.2006, p. 509-516.

Research output: Contribution to journalArticle

Wongsurawat, VJ, Finley, JC, Galipeau, PC, Sanchez, CA, Maley, C, Li, X, Blount, PL, Odze, RD, Rabinovitch, PS & Reid, BJ 2006, 'Genetic mechanisms of TP53 loss of heterozygosity in Barrett's esophagus: Implications for biomarker validation', Cancer Epidemiology Biomarkers and Prevention, vol. 15, no. 3, pp. 509-516. https://doi.org/10.1158/1055-9965.EPI-05-0246
Wongsurawat, V. Jon ; Finley, Jennifer C. ; Galipeau, Patricia C. ; Sanchez, Carissa A. ; Maley, Carlo ; Li, Xiaohong ; Blount, Patricia L. ; Odze, Robert D. ; Rabinovitch, Peter S. ; Reid, Brian J. / Genetic mechanisms of TP53 loss of heterozygosity in Barrett's esophagus : Implications for biomarker validation. In: Cancer Epidemiology Biomarkers and Prevention. 2006 ; Vol. 15, No. 3. pp. 509-516.
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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.",
author = "Wongsurawat, {V. Jon} and Finley, {Jennifer C.} and Galipeau, {Patricia C.} and Sanchez, {Carissa A.} and Carlo Maley and Xiaohong Li and Blount, {Patricia L.} and Odze, {Robert D.} and Rabinovitch, {Peter S.} and Reid, {Brian J.}",
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T1 - Genetic mechanisms of TP53 loss of heterozygosity in Barrett's esophagus

T2 - Implications for biomarker validation

AU - Wongsurawat, V. Jon

AU - Finley, Jennifer C.

AU - Galipeau, Patricia C.

AU - Sanchez, Carissa A.

AU - Maley, Carlo

AU - Li, Xiaohong

AU - Blount, Patricia L.

AU - Odze, Robert D.

AU - Rabinovitch, Peter S.

AU - Reid, Brian J.

PY - 2006/3

Y1 - 2006/3

N2 - 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.

AB - 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.

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