Early events during neoplastic progression in Barrett's esophagus

Abstract

Barrett's esophagus is a condition in which the stratified squamous epithelium of the distal esophagus is replaced by specialized intestinal metaplasia. Clinical management of Barrett's esophagus, like many other "premalignant" conditions, is characterized by overdiagnosis of benign early changes that will not cause death or suffering during the lifetime of an individual and underdiagnosis of life-threatening early disease. Recent studies of a number of different types of cancer have revealed much greater genomic complexity than was previously suspected. This genomic complexity could create challenges for early detection and prevention if it develops in premalignant epithelia prior to cancer. Neoplastic progression unfolds in space and time, and Barrett's esophagus provides one of the best models for rapid advances, including "gold standard" cohort studies, to distinguish individuals who do and do not progress to cancer. Specialized intestinal metaplasia has many properties that appear to be protective adaptations to the abnormal environment of gastroesophageal reflux. A large body of evidence accumulated over several decades implicates chromosome instability in neoplastic progression from Barrett's esophagus to esophageal adenocarcinoma. Small, spatial scale studies have been used to infer the temporal order in which genomic abnormalities develop during neoplastic progression in Barrett's esophagus. These spatial studies have provided the basis for prospective cohort studies of biomarkers, including DNA content abnormalities (tetraploidy, aneuploidy) and a biomarker panel of 9p LOH, 17p LOH and DNA content abnormalities. Recent advances in SNP array technology provide a uniform platform to assess chromosome instability.

Figure 1. Endoscopic biopsies stained with hematoxylin and eosin at 200 magnification

A) stratified squamous epithelium in normal esophagus and B) intestinalized specialized metaplasia in Barrett’s esophagus. (Digital images courtesy of Robert D. Odze, MD, Brigham and Women’s Hospital, Boston Massachusetts.)

Figure 2A. Cumulative EA incidence with combinations of chromosomal biomarker abnormalities (17p LOH, DNA content abnormality, 9p LOH)

Cancer incidence rates are shown for all participants with no selected abnormalities (17p LOH, DNA content abnormalities, or 9p LOH) at baseline (red), any one abnormality (green), any combination of two abnormalities (blue), or all three abnormalities (black).

Figure 2B. Modulation of EA risk by NSAIDs in participants with different baseline abnormalities

Patients are classified according the number of chromosomal biomarker abnormalities, 17p LOH, 9p LOH or any DNA content abnormality (aneuploidy and/or tetraploidy) at baseline. The top two curves represent > 1 baseline abnormality and the lower two curves represent <= 1 abnormality. Shown are Kaplan Meier curves of cancer incidence rates in patients who are NSAID non-users (former or never users) (red) or NSAID users (black).

Figure 3. Clonal evolution in Barrett’s esophagus

The X axis represents time, and the Y axis represents the extent of the Barrett’s segment length. BE arises in a subset of patients in response to the harsh environment of gastroesophageal reflux. Loss of one or both alleles of CDKN2A provides a selective advantage leading to clonal expansion. Neutral mutations also occur during clonal evolution. A neutral mutation arising in a clone with a selected mutation such as those affecting CDKN2A can expand as a hitchhiker on the selected mutation. Otherwise, neutral mutations expand or contract through a random process of genetic drift. TP53 mutations and LOH are selected as later events in neoplastic evolution, almost exclusively in the genetic background of CDKN2A variants. TP53 variants have pleiotropic effects including loss of cell cycle checkpoint control, evasion of apoptosis, and genomic instability that increase genetic diversity within the neoplasm, and they are permissive for subsequent evolution of tetraploid and aneuploid populations. The sizes of genetically unstable clones with TP53 abnormalities and aneuploidy are predictive of future progression to esophageal adenocarcinoma. A panel of chromosomal instability biomarkers (9p, 17p LOH, tetraploidy, aneuploidy) provides independent cancer risk prediction in BE, but mutations in CDKN2A and TP53 and methylation of the CDKN2A promoter do not. A) Illustration of a Barrett’s segment with CDKN2A abnormalities with neutral and hitchhiker mutations. B) Illustration of a Barrett’s segment with expansion of a CDKN2A clone, followed by evolution of a clones with TP53 mutation and 17pLOH that is permissive for evolution of aneuploidy and progression to cancer.