TP53 and cancer: Focal clones with TP53 mutations are common in the normal squamous esophagus5 and localized TP53 + /− clones can be detected in BE that does not progress to ESAD; thus, ultra-deep sequencing would likely identify minority cell populations with TP53 mutations in many patients with BE, but miss the key cancer-promoting feature of clonal expansion of two-hit inactivated TP53. In this study, TP53 −/− cell populations and complex SVs were detected in CO patients an average of 2.2 years prior to the diagnosis of ESAD (range 0.65 - 6.16 years).