Cloning Barretts esophagus stem cells

Barretts esophagus is a precancerous lesion that confers a significant risk of esophageal adenocarcinoma. Strategies for selective eradication of Barretts have been stymied by our inability to identify the Barretts stem cell. Here we employ novel technologies to clone patient-matched stem cells of Barretts, gastric, and esophageal epithelium. Genomic analyses of Barretts stem cells reveal a patient-specific mutational spectrum ranging from low somatic variation similar to patient-matched gastric epithelial stem cells to ones marked by extensive heterozygous alteration of genes implicated in tumor suppression, epithelial planarity, and epigenetic regulation. Transplantation of transformed Barretts stem cells yields tumors with hallmarks of esophageal adenocarcinoma, whereas transformed esophageal stem cells yield squamous cell carcinomas. Thus Barretts develops from cells distinct from local eponymous epithelia, emerges without obvious driver mutations, and likely progresses through and from the generation of dominant clones. These findings define a stem cell target for preemptive therapies of a precancerous lesion.

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Yamamoto Y, Wang X, Bertrand D, Kern F, Zhang T, Duleba M, Srivastava S, Khor CC, Hu Y, Wilson LH, Blaszyk H, Rolshud D, Teh M, Liu J, Howitt BE, Vincent M, Crum CP, Nagarajan N, Ho KY, McKeon F, Xian W