Cloning Barrett’s esophagus stem cells. Homo sapiens

Barrett’s esophagus is a precancerous lesion that confers a significant risk of esophageal adenocarcinoma. Strategies for selective eradication of Barrett’s have been stymied by our inability to identify the Barrett’s stem cell. Here we employ novel technologies to clone patient-matched stem cells of Barrett’s, gastric, and esophageal epithelium. Genomic analyses of Barrett’s 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 Barrett’s stem cells yields tumors with hallmarks of esophageal adenocarcinoma, whereas transformed esophageal stem cells yield squamous cell carcinomas. Thus Barrett’s 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. Overall design: Expression data of Barret's esophagus stem cells cloned from patient biopsy

巴雷特食管（Barrett’s esophagus）是一种癌前病变，可显著提升食管腺癌（esophageal adenocarcinoma）的发病风险。由于尚未能有效识别巴雷特食管干细胞，针对巴雷特食管的选择性根除策略长期以来陷入停滞。本研究借助新型技术手段，成功克隆了患者匹配的巴雷特食管、胃及食管上皮干细胞。对巴雷特食管干细胞的基因组分析结果显示，其存在患者特异性的突变谱：变异程度跨度极大，从与患者匹配的胃上皮干细胞相近的低水平体细胞变异，到以抑癌基因、上皮平面性相关基因及表观遗传调控基因发生广泛杂合性改变为特征的高变异谱。将转化后的巴雷特食管干细胞进行移植，可形成具有食管腺癌特征的肿瘤；而转化后的食管干细胞则会形成鳞状细胞癌。据此可知，巴雷特食管起源于与局部同名上皮截然不同的细胞，在无明显驱动突变的情况下发生，并大概率通过优势克隆的产生实现进展。本研究明确了巴雷特食管这一癌前病变的预防性治疗干细胞靶点。整体实验设计：从患者活检组织中克隆得到的巴雷特食管干细胞的表达数据。