Early detection and pathogenesis during the progression of Barrett's esophagus to esophageal adenocarcinoma

As more studies are needed to gain detailed insight in the pathologic processes during
the transition from SQ epithelium to BE and EAC, the first aim of this thesis is to address
the functional effect of aberrantly expressed proteins and non-coding RNA molecules
and to explore if there are differences in circulating miRNAs between groups of patients
with BE (Part 1). In addition, to optimize current surveillance and treatment strategies,
the second aim of this thesis is to evaluate in detail the risk of malignant progression in
different histological groups of BE patients (Part 2).

Part 1
In Chapter 2 we address the effect of aberrant BMP4 signaling in the pathogenesis of EAC
using in vitro cell culture experiments. Chapter 3 summarizes current knowledge of the
function of differently expressed miRNAs in esophageal cancer. MiRNAs play important
regulatory roles in cancer development and we describe various ways for developing
new treatment modalities. In Chapter 4 we focus on miRNA-203. MiRNA-203 is known to
be downregulated in BE and EAC compared to SQ and we therefore evaluate the role of
miRNA-203 in the development of BE. In Chapter 5, the focus shifts from tissue specific
miRNAs to circulating miRNAs. We explore if there are differences in circulating miRNAs
between healthy controls, patients with BE and EAC, which is the first step in order to
evaluate if circulating miRNAs could be used as biomarker. In Chapter 6 we explore if
circulating miRNAs can be used to identify patients at risk for malignant progression. We
describe miRNA expression profiles in patients with long- and short- segment BE, as patients
with long-segment BE are known to be at a higher risk for malignant progression.

Part 2
In Chapter 7, we describe the risk of malignant progression in BE patients diagnosed
with IND in order to tailor surveillance protocols as current available progression rates
for IND are only based on small (sub)cohort analyses. In Chapter 8, we evaluate the
interobserver variability in the diagnosis of IND in BE as interobser variability is a wellknown
problem in other histological categories of BE. In addition, we evaluate the use of
P53 immunohistochemistry in patients with IND to identify patients at risk of malignant
progression. In Chapter 9 we shift from IND to LGD and report on the effect of persistent
LGD (LGD in repeated biopsy samples) on the risk of malignant progression, in order to
Introduction 15
1 identify a subgroup of LGD patients that could benefit from endoscopic treatment or
intensified endoscopic follow-up.

Part 3
Last, the significance of the results of this thesis are discussed in Chapter 10, and, in
addition, the main findings are summarized in Chapter 11.