Sequencing Highlights the Genetic Progression of Barrett Esophagus to EAC

The progression of Barrett esophagus to esophageal adenocarcinoma (EAC) is thought to involve gradually increasing grades of dysplasia characterized by early loss of the CDKN2A tumor suppressor, followed by clonal expansion, TP53 inactivation, and aneuploidy. However, more recent reports suggest that competition between multiple clones may drive intratumor heterogeneity in EAC. To further understand the transformation of Barrett esophagus to EAC, Stachler and colleagues performed whole-exome sequencing on 25 patient-matched EAC and Barrett esophagus pairs. This analysis revealed no overlap in somatic mutations in 11 of 25 Barrett esophagus–EAC pairs and that the mutation frequency of Barrett esophagus increased with progression to dysplasia and EAC. In contrast, copy-number amplifications were substantially increased in EAC compared with both nondysplastic and dysplastic Barrett esophagus. In clonally related cases and EACs with whole-genome doubling, somatic mutations in TP53, but not CDKN2A, were frequently shared by EAC and adjacent Barrett esophagus and occurred prior to genome duplication, whereas activating oncogenic mutations were uncommon in Barrett esophagus. Consistent with these findings, Ross-Innes, Becq, and colleagues performed whole-genome sequencing of 23 paired Barrett esophagus and EAC samples and found a lack of overlap in mutations between Barrett esophagus and EAC and a significant increase in copy-number alterations during progression to EAC. Analysis of multiple samples harvested from the same patient at different disease stages identified a subset of shared mutations across each of six clones, suggestive of an initial early selective sweep, followed by outgrowth of two clones that harbored additional mutations and led to subsequent seeding of daughter clones. Multiple clones were shown to give rise to regions of high-grade dysplasia and remained stable over time. Together, these findings suggest that genetic variability in Barrett esophagus and multiclonal seeding underlie intratumor heterogeneity in EAC, and that TP53 inactivation followed by genome doubling and late oncogene activation drive EAC development from Barrett esophagus.

Stachler MD, Taylor-Weiner A, Peng S, McKenna A, Agoston AT, Odze RD, et al. Paired exome analysis of Barrett's esophagus and adenocarcinoma. Nat Genet 2015 Jul 20 [Epub ahead of print].

Ross-Innes CS, Becq J, Warren A, Cheetham RK, Northen H, O'Donovan M, et al. Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma. Nat Genet 2015 Jul 20 [Epub ahead of print].