Evolution of Barrett\u2019s esophagus through space and time at single-crypt and whole-biopsy levels

Pierre Martinez,Carlo C Maley,Diego Mallo,Xiaohong Li,Trevor A Graham,Carissa A Sanchez,Thomas G Paulson,Brian J Reid,Mary K Kuhner

doi:10.1038/s41467-017-02621-x

Abstract

The low risk of progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma can lead to over-diagnosis and over-treatment of BE patients. This may be addressed through a better understanding of the dynamics surrounding BE malignant progression. Although genetic diversity has been characterized as a marker of malignant development, it is still unclear how BE arises and develops. Here we uncover the evolutionary dynamics of BE at crypt and biopsy levels in eight individuals, including four patients that experienced malignant progression. We assay eight individual crypts and the remaining epithelium by SNP array for each of 6–11 biopsies over 2 time points per patient (358 samples in total). Our results indicate that most Barrett’s segments are clonal, with similar number and inferred rates of alterations observed for crypts and biopsies. Divergence correlates with geographical location, being higher near the gastro-esophageal junction. Relaxed clock analyses show that genomic instability precedes and is enhanced by genome doubling. These results shed light on the clinically relevant evolutionary dynamics of BE.

Highlights

The low risk of progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma can lead to over-diagnosis and over-treatment of BE patients
Previous analyses of individual crypts have been restricted to a single time point and only a few loci per crypt[8], whereas most other studies have analyzed whole biopsies, comprising hundreds of crypts; virtually, everything we know about the evolutionary dynamics of neoplastic progression in BE is based on studies of whole biopsies
Genome doubling (GD) and high levels of space. Copy number alteration (SCA) were detectable in most individuals who later developed esophageal adenocarcinoma (EAC) 4 years before progression, whereas SCA levels remained low in most nonprogressors[11]

Summary

Introduction

The low risk of progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma can lead to over-diagnosis and over-treatment of BE patients. This may be addressed through a better understanding of the dynamics surrounding BE malignant progression. We uncover the evolutionary dynamics of BE at crypt and biopsy levels in eight individuals, including four patients that experienced malignant progression. Barrett’s esophagus (BE) is a neoplastic lesion of the esophagus that predisposes to esophageal adenocarcinoma (EAC)[1] It is an ideal model for studying the dynamics of somatic evolution, because the standard of care requires longitudinal and multi-region sampling, cataloging evolution across both space and time. Single-crypt analyses can distinguish between these alternative hypotheses, providing evidence on the dynamics and mode of progression from BE to EAC

Methods

Results

Conclusion