Clonal selection and persistence in dysplastic Barrett's esophagus and intramucosal cancers after failed radiofrequency ablation.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
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.
Sebastian S
SS
Zeki
Rehan
R
Haidry
Trevor A
TA
Graham
Manuel
M
Rodriguez-Justo
Marco
M
Novelli
Jonathon
J
Hoare
Jason
J
Dunn
Nicholas A
NA
Wright
Laurence B
LB
Lovat
Stuart A C
SA
McDonald
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D017115:Catheter Ablation; D060965:Clonal Evolution; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D004945:Esophagoscopy; D004947:Esophagus / Q000473:pathology* / Q000601:surgery; D005260:Female; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D061346:Laser Capture Microdissection; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000473:pathology* / Q000601:surgery; D016133:Polymerase Chain Reaction; D017211:Treatment Failure