TY - JOUR
T1 - The combination of genetic instability and clonal expansion predicts progression to esophageal adenocarcinoma
AU - Maley, Carlo C.
AU - Galipeau, Patricia C.
AU - Li, Xiaohong
AU - Sanchez, Carissa A.
AU - Paulson, Thomas G.
AU - Blount, Patricia L.
AU - Reid, Brian J.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/10/15
Y1 - 2004/10/15
N2 - There is debate in the literature over the relative importance of genetic instability and clonal expansion during progression to cancer. Barrett's esophagus is a uniquely suited model to investigate neoplastic progression prospectively because periodic endoscopic biopsy surveillance is recommended for early detection of esophageal adenocarcinoma. We hypothesized that expansion of clones with genetic instability would predict progression to esophageal adenocarcinoma. We measured p16 (CDKN2A/ INK4A) lesions (loss of heterozygosity, mutations, and CpG island methylation), p53 (TP53) lesions (loss of heterozygosity, mutation) and ploidy abnormalities (aneuploidy, tetraploidy) within each Barrett's esophagus segment of a cohort of 267 research participants, who were followed prospectively with cancer as an outcome. We defined the size of a lesion as the fraction of cells with the lesion multiplied by the length of the Barrett's esophagus segment. A Cox proportional hazards regression indicates that the sizes of clones with p53 loss of heterozygosity (relative risk = 1.2x for an x cm clone; 95% confidence interval, 1.07-1.50) or ploidy abnormalities (relative risk = 1.31x for an x cm clone; 95% confidence interval, 1.07-1.60) predict progression to esophageal adenocarcinoma better than the mere presence of such clones (likelihood ratio test, P < 0.01). Controlling for length of the Barrett's esophagus segment had little effect. The size of a clone with a p16 lesion is not a significant predictor of esophageal adenocarcinoma when we controlled for p53 loss of heterozygosity status. The combination of clonal expansion and genetic instability is a better predictor of cancer outcome than either alone. This implies that interventions that limit expansion of genetically unstable clones may reduce risk of progression to cancer.
AB - There is debate in the literature over the relative importance of genetic instability and clonal expansion during progression to cancer. Barrett's esophagus is a uniquely suited model to investigate neoplastic progression prospectively because periodic endoscopic biopsy surveillance is recommended for early detection of esophageal adenocarcinoma. We hypothesized that expansion of clones with genetic instability would predict progression to esophageal adenocarcinoma. We measured p16 (CDKN2A/ INK4A) lesions (loss of heterozygosity, mutations, and CpG island methylation), p53 (TP53) lesions (loss of heterozygosity, mutation) and ploidy abnormalities (aneuploidy, tetraploidy) within each Barrett's esophagus segment of a cohort of 267 research participants, who were followed prospectively with cancer as an outcome. We defined the size of a lesion as the fraction of cells with the lesion multiplied by the length of the Barrett's esophagus segment. A Cox proportional hazards regression indicates that the sizes of clones with p53 loss of heterozygosity (relative risk = 1.2x for an x cm clone; 95% confidence interval, 1.07-1.50) or ploidy abnormalities (relative risk = 1.31x for an x cm clone; 95% confidence interval, 1.07-1.60) predict progression to esophageal adenocarcinoma better than the mere presence of such clones (likelihood ratio test, P < 0.01). Controlling for length of the Barrett's esophagus segment had little effect. The size of a clone with a p16 lesion is not a significant predictor of esophageal adenocarcinoma when we controlled for p53 loss of heterozygosity status. The combination of clonal expansion and genetic instability is a better predictor of cancer outcome than either alone. This implies that interventions that limit expansion of genetically unstable clones may reduce risk of progression to cancer.
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U2 - 10.1158/0008-5472.CAN-04-1738
DO - 10.1158/0008-5472.CAN-04-1738
M3 - Article
C2 - 15492292
AN - SCOPUS:5644255657
VL - 64
SP - 7629
EP - 7633
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 20
ER -