TY - JOUR
T1 - Temporal and spatial evolution of somatic chromosomal alterations
T2 - A case-cohort study of Barrett's esophagus
AU - Li, Xiaohong
AU - Galipeau, Patricia C.
AU - Paulson, Thomas G.
AU - Sanchez, Carissa A.
AU - Arnaudo, Jessica
AU - Liu, Karen
AU - Sather, Cassandra L.
AU - Kostadinov, Rumen L.
AU - Odze, Robert D.
AU - Kuhner, Mary K.
AU - Maley, Carlo C.
AU - Self, Steven G.
AU - Vaughan, Thomas L.
AU - Blount, Patricia L.
AU - Reid, Brian J.
PY - 2014/1
Y1 - 2014/1
N2 - All cancers are believed to arise by dynamic, stochastic somatic genomic evolution with genome instability, generation of diversity, and selection of genomic alterations that underlie multistage progression to cancer. Advanced esophageal adenocarcinomas have high levels of somatic copy number alterations. Barrett's esophagus is a risk factor for developing esophageal adenocarcinoma, and somatic chromosomal alterations (SCA) are known to occur in Barrett's esophagus. The vast majority (~95%) of individuals with Barrett's esophagus do not progress to esophageal adenocarcinoma during their lifetimes, but a small subset develop esophageal adenocarcinoma,many ofwhich arise rapidly even in carefullymonitored patients without visible endoscopic abnormalities at the index endoscopy. Using a well-designed, longitudinal case-cohort study, we characterized SCA as assessed by single-nucleotide polymorphism arrays over space and time in 79*progressors*with Barrett's esophagus as they approach the diagnosis of cancer and 169*nonprogressors*with Barrett's esophaguswho did not progress to esophageal adenocarcinomaover more than 20,425 personmonths of follow-up. The genomes of nonprogressors typically had small localized deletions involving fragile sites and 9p loss/copy neutral LOH that generate little genetic diversity and remained relatively stable over prolonged follow-up. As progressors approach the diagnosis of cancer, their genomes developed chromosome instability with initial gains and losses, genomic diversity, and selection of SCAs followed by catastrophic genome doublings. Our results support a model of differential disease dynamics in which nonprogressor genomes largely remain stable over prolonged periods, whereas progressor genomes evolve significantly increased SCA and diversity within four years of esophageal adenocarcinoma diagnosis, suggesting a window of opportunity for early detection.
AB - All cancers are believed to arise by dynamic, stochastic somatic genomic evolution with genome instability, generation of diversity, and selection of genomic alterations that underlie multistage progression to cancer. Advanced esophageal adenocarcinomas have high levels of somatic copy number alterations. Barrett's esophagus is a risk factor for developing esophageal adenocarcinoma, and somatic chromosomal alterations (SCA) are known to occur in Barrett's esophagus. The vast majority (~95%) of individuals with Barrett's esophagus do not progress to esophageal adenocarcinoma during their lifetimes, but a small subset develop esophageal adenocarcinoma,many ofwhich arise rapidly even in carefullymonitored patients without visible endoscopic abnormalities at the index endoscopy. Using a well-designed, longitudinal case-cohort study, we characterized SCA as assessed by single-nucleotide polymorphism arrays over space and time in 79*progressors*with Barrett's esophagus as they approach the diagnosis of cancer and 169*nonprogressors*with Barrett's esophaguswho did not progress to esophageal adenocarcinomaover more than 20,425 personmonths of follow-up. The genomes of nonprogressors typically had small localized deletions involving fragile sites and 9p loss/copy neutral LOH that generate little genetic diversity and remained relatively stable over prolonged follow-up. As progressors approach the diagnosis of cancer, their genomes developed chromosome instability with initial gains and losses, genomic diversity, and selection of SCAs followed by catastrophic genome doublings. Our results support a model of differential disease dynamics in which nonprogressor genomes largely remain stable over prolonged periods, whereas progressor genomes evolve significantly increased SCA and diversity within four years of esophageal adenocarcinoma diagnosis, suggesting a window of opportunity for early detection.
UR - http://www.scopus.com/inward/record.url?scp=84892427011&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892427011&partnerID=8YFLogxK
U2 - 10.1158/1940-6207.CAPR-13-0289
DO - 10.1158/1940-6207.CAPR-13-0289
M3 - Article
C2 - 24253313
AN - SCOPUS:84892427011
SN - 1940-6207
VL - 7
SP - 114
EP - 127
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 1
ER -