Cell proliferation, cell cycle abnormalities, and cancer outcome in patients with Barrett's esophagus: a long-term prospective study.
OBJECTIVE
Elevated cellular proliferation and cell cycle abnormalities, which have been associated with premalignant lesions, may be caused by inactivation of tumor suppressor genes. We measured proliferative and cell cycle fractions of biopsies from a cohort of patients with Barrett's esophagus to better understand the role of proliferation in early neoplastic progression and the association between cell cycle dysregulation and tumor suppressor gene inactivation.


METHODS
Cell proliferative fractions (determined by Ki67/DNA multiparameter flow cytometry) and cell cycle fractions (DNA content flow cytometry) were measured in 853 diploid biopsies from 362 patients with Barrett's esophagus. The inactivation status of CDKN2A and TP53 was assessed in a subset of these biopsies in a cross-sectional study. A prospective study followed 276 of the patients without detectable aneuploidy for an average of 6.3 years with esophageal adenocarcinoma as an end point.


RESULTS
Diploid S and 4N (G(2)/tetraploid) fractions were significantly higher in biopsies with TP53 mutation and loss of heterozygosity. CDKN2A inactivation was not associated with higher Ki67-positive, diploid S, G(1), or 4N fractions. High Ki67-positive and G(1)-phase fractions were not associated with the future development of esophageal adenocarcinoma (P=0.13 and P=0.15, respectively), whereas high diploid S-phase and 4N fractions were (P=0.03 and P<0.0001, respectively).


CONCLUSIONS
High Ki67-positive proliferative fractions were not associated with inactivation of CDKN2A and TP53 or future development of cancer in our cohort of patients with Barrett's esophagus. Biallelic inactivation of TP53 was associated with elevated 4N fractions, which have been associated with the future development of esophageal adenocarcinoma.
Chao
Dennis L
DL
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. dchao@fhcrc.org
Sanchez
Carissa A
CA
Galipeau
Patricia C
PC
Blount
Patricia L
PL
Paulson
Thomas G
TG
Cowan
David S
DS
Ayub
Kamran
K
Odze
Robert D
RD
Rabinovitch
Peter S
PS
Reid
Brian J
BJ
D000230:Adenocarcinoma / Q000175:diagnosis / Q000473:pathology*; D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000150:complications* / Q000473:pathology*; D002453:Cell Cycle; D002455:Cell Division; D015331:Cohort Studies; D004938:Esophageal Neoplasms / Q000209:etiology / Q000473:pathology*; D005260:Female; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008137:Longitudinal Studies; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies
D019394:Ki-67 Antigen