p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium.
Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma, a cancer of which the incidence has been increasing at an alarming rate in Western countries. p16(INK4a) lesions occur frequently in esophageal adenocarcinomas but their role in neoplastic progression is not well understood. We detected 9p21 loss of heterozygosity, p16 CpG island methylation, and p16 mutations in biopsies from 57%, 61%, and 15%, respectively, of 107 patients with BE. In contrast, no mutations were found in p14(ARF) or p15, and methylation was found in only 4% and 13%, respectively. >85% of Barrett's segments had clones with one (p16+/-) or two (p16-/-) p16 lesions. Both p16+/- and p16-/- clones underwent extensive expansion involving up to 17 cm of esophageal mucosa. The prevalence of established biomarkers in BE, such as 17p (p53) loss of heterozygosity, aneuploidy, and/or increased 4N (tetraploid) populations, increased from 0% to 20% to 44% in patients whose biopsies were p16+/+, p16+/-, and p16-/-, respectively (P < 0.001). Barrett's segment lengths also increased with change in p16 status with a median of 1.5, 6.0, and 8.0 cm for patients with p16+/+, p16+/-, and p16-/- biopsies, respectively (P < 0.001). We conclude that most Barrett's metaplasia contains genetic and/or epigenetic p16 lesions and has the ability to undergo clonal expansion, creating a field in which other abnormalities can arise that can lead to esophageal adenocarcinoma.
Wong
D J
DJ
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Paulson
T G
TG
Prevo
L J
LJ
Galipeau
P C
PC
Longton
G
G
Blount
P L
PL
Reid
B J
BJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D001706:Biopsy; D002899:Chromosomes, Human, Pair 9; D002999:Clone Cells; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D004847:Epithelial Cells / Q000473:pathology; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology; D006801:Humans; D019656:Loss of Heterozygosity; D008677:Metaphase / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology
D019941:Cyclin-Dependent Kinase Inhibitor p16