Temporal and Spatial Evolution of Somatic Chromosomal Alterations: A Case-Cohort Study of Barrett's Esophagus

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 multi-stage progression to cancer. Advanced esophageal adenocarcinomas (EAs) have high levels of somatic copy number alterations. Barrett’s esophagus (BE) is a risk factor for developing EA, and somatic chromosomal alterations (SCAs) are known to occur in BE. The vast majority (~95%) of individuals with BE do not progress to EA during their lifetimes, but a small subset develop EA, 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 SNP arrays over space and time in 79 “progressors” with BE as they approach the diagnosis of cancer and 169 “nonprogressors” with BE who did not progress to EA over 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 EA diagnosis, suggesting a window of opportunity for early detection.

Quantification of multiple tumor clones using gene array and sequencing data

“…This observation is supported by the data in previous studies (Li, 2014; Gu et al, 2010). We showed that such correlation pertains to probes that are distant away (e.g.…”

Clonal Evolution: Multiregion Sequencing of Esophageal Adenocarcinoma Before and After Chemotherapy

“…TP53 mutations, chromosomal instability, and genome duplication were observed in nearly all samples as early events. These fi ndings support the results from a previous longitudinal case-control study that showed increased chromosomal instability, genome duplication, and genome diversity in samples obtained from patients with Barrett's esophagus as they approached the diagnosis of esophageal adenocarcinoma ( 6 ).…”

Evolution of Premalignant Disease

“…In both cancer progressors and nonprogressors, large, stable clones have been found that consist of cells with loss of heterozygosity (LOH) for chromosomes 9p and 17p in BE (Buas et al 2014;Li et al 2014) and those with distinct CpG island methylation signatures in colorectal adenomas (Luo et al 2014.). As mentioned previously, a field effect caused by early common mutations in TP53 have also been found in BE segments , and similarly in patients with UC (Leedham et al 2009;Galandiuk et al 2012) and lung cancer patients (Franklin et al 1997;de Bruin et al 2014;Pipinikas et al 2014).…”