PMID- 16537709
OWN - NLM
STAT- MEDLINE
DCOM- 20060719
LR  - 20191210
IS  - 1055-9965 (Print)
IS  - 1055-9965 (Linking)
VI  - 15
IP  - 3
DP  - 2006 Mar
TI  - Genetic mechanisms of TP53 loss of heterozygosity in Barrett's esophagus: 
      implications for biomarker validation.
PG  - 509-16
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.
FAU - Wongsurawat, V Jon
AU  - Wongsurawat VJ
AD  - Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer 
      Research Center, Seattle, WA 98109, USA.
FAU - Finley, Jennifer C
AU  - Finley JC
FAU - Galipeau, Patricia C
AU  - Galipeau PC
FAU - Sanchez, Carissa A
AU  - Sanchez CA
FAU - Maley, Carlo C
AU  - Maley CC
FAU - Li, Xiaohong
AU  - Li X
FAU - Blount, Patricia L
AU  - Blount PL
FAU - Odze, Robert D
AU  - Odze RD
FAU - Rabinovitch, Peter S
AU  - Rabinovitch PS
FAU - Reid, Brian J
AU  - Reid BJ
LA  - eng
GR  - P01 CA91955/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Validation Study
PL  - United States
TA  - Cancer Epidemiol Biomarkers Prev
JT  - Cancer epidemiology, biomarkers & prevention : a publication of the American 
      Association for Cancer Research, cosponsored by the American Society of 
      Preventive Oncology
JID - 9200608
RN  - 0 (Biomarkers, Tumor)
SB  - IM
MH  - Adenocarcinoma/*genetics/mortality/pathology
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Barrett Esophagus/*genetics/mortality/pathology
MH  - Biomarkers, Tumor/analysis
MH  - Esophageal Neoplasms/*genetics/mortality/pathology
MH  - Esophagectomy
MH  - Esophagoscopy
MH  - Female
MH  - *Genes, p53
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - *Loss of Heterozygosity
MH  - Male
MH  - Neoplasm Staging
MH  - Precancerous Conditions/*pathology
MH  - Prognosis
MH  - Retrospective Studies
MH  - Risk Assessment
MH  - Sensitivity and Specificity
MH  - Survival Rate
EDAT- 2006/03/16 09:00
MHDA- 2006/07/20 09:00
CRDT- 2006/03/16 09:00
PHST- 2006/03/16 09:00 [pubmed]
PHST- 2006/07/20 09:00 [medline]
PHST- 2006/03/16 09:00 [entrez]
AID - 15/3/509 [pii]
AID - 10.1158/1055-9965.EPI-05-0246 [doi]
PST - ppublish
SO  - Cancer Epidemiol Biomarkers Prev. 2006 Mar;15(3):509-16. doi: 
      10.1158/1055-9965.EPI-05-0246.