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Cell proliferation, cell cycle abnormalities, and cancer outcome in patients with Barrett’s esophagus: A long-term prospective study

Chao, Dennis L. and Sanchez, Carissa A. and Galipeau, Patricia C. and Blount, Patricia L. and Paulson, Thomas G. and Cowan, David S. and Ayub, Kamran and Odze, Robert D. and Rabinovitch, Peter S. and Reid, Brian J. (2008) Cell proliferation, cell cycle abnormalities, and cancer outcome in patients with Barrett’s esophagus: A long-term prospective study. Clinical Cancer Research, 14 (21). pp. 6988-6995. ISSN 1078-0432

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Article URL: http://clincancerres.aacrjournals.org/cgi/reprint/...

Abstract

Purpose: 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. Experimental Design: 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 endpoint. Results: Diploid S and 4N (G2/tetraploid) fractions were significantly higher in biopsies with TP53 mutation and LOH. CDKN2A inactivation was not associated with higher Ki67-positive, diploid S, G1, or 4N fractions. High Ki67-positive and G1 phase fractions were not associated with the future development of esophageal adenocarcinoma (p=0.13 and p=0.15, respectively), while 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. Bi-allelic inactivation of TP53 was associated with elevated 4N fractions, which have been associated with the future development of esophageal adenocarcinoma.

Item Type: Article
Additional Information: This article is available to subscribers only via the URL above for the first 12 month following publication.
DOI: 10.1158/1078-0432.CCR-07-5063
PubMed ID: 18980994
NIHMSID: NIHMS72445
PMCID: PMC2587072
Grant Numbers: P01 CA091955-06, R01 CA061202-08, T32 CA080416-10, K07 CA089147-05
Keywords or MeSH Headings: * Adenocarcinoma/diagnosis * Adenocarcinoma/pathology* * Adult * Aged * Barrett Esophagus/complications* * Barrett Esophagus/pathology* * Cell Cycle* * Cell Division* * Cohort Studies * Esophageal Neoplasms/etiology * Esophageal Neoplasms/pathology* * Female * Genes, p16 * Genes, p53 * Humans * Ki-67 Antigen/metabolism * Longitudinal Studies * Loss of Heterozygosity * Male * Middle Aged * Mutation * Prospective Studies
Subjects: Diseases > Solid tumors > Digestive system cancer
Cellular and Organismal Processes > Cell Physiology > Cell proliferation
Cellular and Organismal Processes > Cell Physiology > Cell cycle
Depositing User: Library Staff
Date Deposited: 03 Oct 2008 22:20
Last Modified: 14 Feb 2012 14:42
URI: http://authors.fhcrc.org/id/eprint/84

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