Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
Am J Gastroenterol. 2013 Oct;108(10):1584-92. doi: 10.1038/ajg.2013.238. Epub 2013 Aug 13.
Radiofrequency ablation (RFA) is used to successfully eliminate Barrett's esophagus (BE)-related dysplasia or intramucosal carcinoma and aims to cause reversion to squamous epithelium. However, in 20% of cases RFA fails to return the epithelium to squamous phenotype. Follow-up studies show a similar dysplasia recurrence rate. We hypothesize that failed RFA is due to clonally mutated epithelial populations harbored in RFA-privileged sites and that RFA can select for the mutant clonal expansion.
A longitudinal case series of 19 patients with BE and high-grade dysplasia or intramucosal carcinoma were studied. DNA was extracted from individual Barrett's glands, deep esophageal glands within mucosal resections and biopsy specimens before and after RFA. Mutations were identified by targeted sequencing of genes commonly mutated in Barrett's adenocarcinoma.
Five patients demonstrated persistent post-RFA pathology with persistent mutations, sometimes detected in deep esophageal glands or neighboring squamous epithelium after several rounds of RFA preceded by mucosal resection. Recurrence of pathology in three other patients was characterized by de novo mutations.
Protumorigenic mutations can be found in post-ablation squamous mucosa as well as in mutant deep esophageal glands; both are associated with dysplasia recurrence. Following RFA, non-dysplastic Barrett's epithelium can contain mutant clones that are found in a subsequent adenocarcinoma. Ablation may also drive the clonal expansion of pre-existing clones after a "bottleneck" created by the RFA. Overall, recurrence of dysplasia post RFA reflects the multicentric origins of Barrett's clones and highlights the role of clonal selection in carcinogenesis.
射频消融（RFA）用于成功消除 Barrett 食管（BE）相关异型增生或黏膜内癌，并旨在促使上皮恢复为鳞状上皮。然而，在 20%的情况下，RFA 未能使上皮恢复为鳞状表型。随访研究显示类似的异型增生复发率。我们假设 RFA 失败是由于 RFA 有利部位中存在克隆突变的上皮群体，并且 RFA 可以选择突变克隆的扩增。
对 19 例 BE 伴高级别异型增生或黏膜内癌患者进行了一项纵向病例系列研究。从 RFA 前后的单个 Barrett 腺、黏膜切除的深部食管腺和活检标本中提取 DNA。通过针对 Barrett 腺癌中常见突变基因的靶向测序来鉴定突变。
5 例患者表现出持续的 RFA 后病理学表现，在多次 RFA 之前的黏膜切除后，在深部食管腺或邻近的鳞状上皮中有时会检测到持续的突变。另外 3 例患者的病理学复发特征为新出现的突变。
在 RFA 后鳞状黏膜以及突变的深部食管腺中都可以发现促肿瘤基因突变；两者均与异型增生复发有关。RFA 后，非异型增生的 Barrett 上皮可能含有随后腺癌中发现的突变克隆。消融也可能在 RFA 造成的“瓶颈”后推动先前存在的克隆的克隆扩增。总体而言，RFA 后异型增生的复发反映了 Barrett 克隆的多中心起源，并强调了克隆选择在致癌作用中的作用。
