Milea Timbergen

334 Summary This thesis consists of four parts. Part I of this thesis aims to gain insight into the genetics and biology of desmoid-type fibromatosis (DTF). The first chapter describes the role of the various cell signalling pathways. The other chapters aim to explain potential differences in clinical behaviour by comparing Wingless (Wnt)/ β-catenin signalling and DNA methylation patterns of the most common CTNNB1 mutation types. Part II describes a novel technique named radiomics, evaluates the success of the active surveillance approach and investigates whether primary S45F-mutated DTF tumours have an increased risk on recurrence after surgery. Part III describes the health-related quality of life (HRQoL) in the setting of DTF. Part I - Genetics and Molecular Biology Chapter 2 describes the current evidence for the use of targeted therapies in the treatment of DTF. Specific attention was paid to in vivo / in vitro studies. This literature review aimed to review the common cell signalling pathways Wnt/β-catenin, JAK/STAT, Notch, PI3 kinase/ AKT, mTOR, Hedgehog, the oestrogen pathway, and the growth regulatory pathway, which might play a role in the pathogenesis of DTF. Additionally, an overview on the currently available targeted therapies targeting the aforementioned pathways is provided. This review underlined the existing evidence for activation of the Wnt/β-catenin cell signalling pathway, but currently there are no clinically available treatments targeting this pathway. The evidence for activation of the other signalling pathways is weak and mainly based on the expression of certain genes or reports of observed clinical response after treatment with available targeted therapies. Currently, few randomized clinical trials investigate the effect of targeted therapies. This study raises awareness to the need to better understand the biology of DTF and identify novel therapeutic drug targets. Chapter 3 describes the role of the Wnt/β-catenin cell signalling pathway. β-catenin is a major player in this pathway and this chapter investigated the differences in expression of Wnt-related genes between the different mutation types of DTF (S45F, T41A, S45P and wild-type (WT)). This study uses mRNA data of 128 desmoid patients from an Affymetrix dataset (gene Expression Omnibus series matrix file, GSE58697). Additionally, the expression of AXIN2 , CCND1 , and DKK1 was calculated in 64 desmoid patients by real-time polymerase chain reactions (RT-PCR). There were no statistically significant differences in relative expression levels of the Wnt-related genes AXIN2 , CCND1 , and DKK1 between the β-catenin mutants. Hierarchical cluster analyses using selected Wnt targets did not discriminate between different CTNNB1 mutation types. 13