Milea Timbergen

318 The biological explanation for the aforementioned differences remains unclear. In pre- clinical research studying liver cancer, different CTNNB1 mutations are linked to different levels of β-catenin activation: an S45F mutations led to a weaker activation compared to T41A, but the duplication of weak S45F alleles resulted in a final higher β-catenin activity 36 . In desmoid cells, Hamada et al. reported that S45F desmoid cells have a stronger nuclear β-catenin staining and observed an upregulation of Wnt target genes AXIN2 and CCND1 compared to WT and T41A cells 37 . In this thesis we sought to explain these clinical differences based on mRNA expression data and DNA methylation patterns. In Chapter 3 , we compared Wnt signalling activity between the mutation types based on the expression of Wnt target genes. We were not able to identify differences comparing the different mutations types. In Chapter 4 , we used a novel technique to uncover whole genome DNA- methylation patterns. No distinct DNA-methylation patterns were found between DTF with a S45F or T41A mutation. From this research we tentatively conclude that S45F and T41A are biologically similar and that observed clinical differences may be caused by other factors such as tumour location or size 38 . A possible confounder in our studies is that the WT group, now defined by the absence of mutations in exon 3 of CTNNB1 , needs to be screened more thoroughly for CTNNB1 mutations. This group of DTF tumours remain peculiar, as previous studies show that a large part of these “wild-type” contain other mutations in APC or CTNNB1 which can be detected using more sensitive methods than Sanger Sequencing (e.g., Next Generation Sequencing) 39, 40 . In this group, other genomic alterations can occur like APC loss, chromosome 6 loss and alterations such as BMI1 mutations are seen. All of these alterations are linked to Wnt/β-catenin activation 40 and this pathway seems to play a pivotal role in the development of DTF tumours. More insight into the genes that drive this subgroup of tumours and their biological and clinical differences with the more common mutation is encouraged. Diagnosis and Treatment About one third of DTF patients is misdiagnosed at the first presentation 41 . Early recognition and referral to a sarcoma centre with a medical specialist with affinity for DTF, is vital for a patient to establish a correct diagnosis and treatment plan 3 . Magnetic resonance imaging (MRI) is the preferred imaging modality for extra-abdominal or abdominal wall soft tissue sarcomas (STS) and DTF. However, these two entities can display similar imaging characteristics such as fascial crossing and invasive growth 42 . As DTF is rare, there are no established imaging protocols and diagnosing can be challenging. Radiomics is a promising technique that links large amounts of quantitative imaging features with 11