Session I: Barrett’s esophagus Spatial and temporal heterogeneity in Barrett’s esophagus

Within a neoplasm, there is genetic heterogeneity over both space and time. This heterogeneity is a fundamental property of the clonal evolution that drives neoplastic progression. It also poses unique challenges to the development of screening strategies and biomarkers for risk stratification and early detection of cancer. False negative results on assays may be due to a failure to sample the relevant clone in a neoplasm. Furthermore, the predictive power of accurate information gained from screening may decay with time as the neoplasm changes through the stochastic appearance and extinction of mutant clones. We have shown in premalignant Barrett’s esophagus (BE) that mutant clones may cover complex, concave shapes on the surface of the esophagus. Within the Barrett’s neoplasms, genetic heterogeneity in space predicts progression to cancer. We have also found that the risk of progression associated with loss of heterozygosity in p16 (CDKN2A/INK4A) decreases with time since biopsy. The ability to image the different clones in a neoplasm would allow the targeted sampling of mutations associated with risk of progression. Imaging of clones would help to illuminate how clones expand and go extinct in a neoplasm, allowing intervention in those processes to prevent or delay progression to malignancy.