Temporal and Spatial Evolution of Somatic Chromosomal Alterations: A Case-Cohort Study of Barrett's Esophagus
- 1 January 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Prevention Research
- Vol. 7 (1), 114-127
- https://doi.org/10.1158/1940-6207.capr-13-0289
Abstract
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 of which arise rapidly even in carefully monitored 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 esophagus who did not progress to esophageal adenocarcinoma over more than 20,425 person-months 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. Cancer Prev Res; 7(1); 114–27. ©2013 AACR.Other Versions
This publication has 70 references indexed in Scilit:
- Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexityNature Genetics, 2013
- The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroupsNature, 2012
- Clonal evolution in cancerNature, 2012
- American Gastroenterological Association Technical Review on the Management of Barrett's EsophagusGastroenterology, 2011
- Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer DevelopmentCell, 2011
- Dr Jekyll and Mr Hyde: role of aneuploidy in cellular adaptation and cancerCurrent Opinion in Cell Biology, 2010
- Distant metastasis occurs late during the genetic evolution of pancreatic cancerNature, 2010
- Principles of Cancer Screening: Lessons From History and Study Design IssuesSeminars in Oncology, 2010
- The landscape of somatic copy-number alteration across human cancersNature, 2010
- Barrett's oesophagus and oesophageal adenocarcinoma: time for a new synthesisNature Reviews Cancer, 2010