Mutagen sensitivity and neoplastic progression in patients with Barrett's esophagus: a prospective analysis.
BACKGROUND
Defects in DNA damage recognition and repair have been associated with a wide variety of cancers. We conducted a prospective study to determine whether mutagen sensitivity, as determined by an in vitro assay, was associated with the future development of cancer in patients with Barrett's esophagus, which is associated with increased risk of progression to esophageal adenocarcinoma.


METHODS
We measured sensitivity to bleomycin in peripheral blood lymphocytes in a cohort of 220 patients with Barrett's esophagus. We followed these patients for 1,230 person-years (range, 3 months to 10.1 years; median, 6.4 years), using development of cancer and aneuploidy as end points. A subset of these patients was evaluated for inactivation of tumor-suppressor genes CDKN2A/p16 and TP53 [by mutation and loss of heterozygosity (LOH)] in their Barrett's segments at the time of, or before, the bleomycin test, and the patients were stratified by CDKN2A/p16 and TP53 status in an analysis of mutagen sensitivity and progression.


RESULTS
Bleomycin-sensitive patients were found to be at significantly greater risk of developing aneuploidy (adjusted hazard ratio, 3.71; 95% confidence interval, 1.44-9.53) and nonsignificantly greater risk of cancer (adjusted hazard ratio, 1.63; 95% confidence interval, 0.71-3.75). Among patients with detectable LOH at the TP53 locus (on chromosome 17p), increasing bleomycin sensitivity was associated with increased risk of developing cancer (P(trend) < 0.001) and aneuploidy (P(trend) = 0.005).


CONCLUSIONS
This study supports the hypothesis that sensitivity to mutagens increases the risk of neoplastic progression in persons with Barrett's esophagus, particularly those with 17p LOH including TP53.
Chao
Dennis L
DL
Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, C1-157, Seattle, WA 98109, USA. dchao@fhcrc.org
Maley
Carlo C
CC
Wu
Xifeng
X
Farrow
Diana C
DC
Galipeau
Patricia C
PC
Sanchez
Carissa A
CA
Paulson
Thomas G
TG
Rabinovitch
Peter S
PS
Reid
Brian J
BJ
Spitz
Margaret R
MR
Vaughan
Thomas L
TL
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D000328:Adult; D000368:Aged; D000782:Aneuploidy; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001471:Barrett Esophagus / Q000150:complications / Q000235:genetics / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001761:Bleomycin / Q000494:pharmacology; D019457:Chromosome Breakage / Q000187:drug effects; D002886:Chromosomes, Human, Pair 17 / Q000187:drug effects / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000235:genetics; D019942:Genes, p16; D016158:Genes, p53 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000032:analysis*; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011446:Prospective Studies; D012680:Sensitivity and Specificity
D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D009153:Mutagens; D001761:Bleomycin