Milea Timbergen

93 Introduction Desmoid-type fibromatosis (DTF) is a rare, non-metastasizing, invasive, mesenchymal soft tissue sarcoma 1, 2 . The presence 3 of nuclear β-catenin distinguishes DTF from other soft tissue tumours and scar tissue 4 and is caused by the fact that the majority of tumours (> 85%) harbor a mutation at specific sites in the β-catenin ( CTNNB1 ) gene 5 . These mutually exclusive mutations in exon 3 of the CTNNB1 gene result in substitution of serine at position 45 with phenylalanine (S45F), or less commonly proline (S45P), or lead to a replacement of threonine at position 41 with alanine (T41A) 5, 6 . The tumour is categorized as wild-type (WT) in case no CTNNB1 exon 3 mutations are found. This WT group is considered heterogeneous as these tumours may contain other CTNNB1 , outside of exon 3, or APC mutations 5 . Despite the shared molecular basis in the majority of DTF patients, the clinical presentation and disease course varies. Several studies indicate a prognostic role for the CTNNB1 mutation and some claim that S45F tumours have a higher risk of recurrence after surgery in comparison to T41A tumours 6-8 or that S45F tumours are more resistant to treatment with e.g., sorafenib 9 , doxorubicin 10 or meloxicam 11 . Currently, there is no biological rationale for the reported clinical differences in behaviour – particularly the risk of recurrence - of DTF with these mutation types. A recent pilot study revealed differences in the metabolomics profiles associated with T41A and S45F DTF cell lines also suggesting that - up to a certain extent - the biology of DTF with these CTNNB1 mutations indeed differs 12 . The CTNNB1 mutations that are predominantly observed in DTF, prevent phosphorylation and subsequent degradation of β-catenin, a key player in the Wnt/β-catenin signalling pathway. This leads to stabilisation and translocation of β-catenin into the nucleus, causing aberrant Wnt/β-catenin signalling. However, CTNNB1 has a complex role in the cell, and is involved in protein-interaction networks related to cell adhesion and transcription. Nuclear β-catenin recruits transcription factors of the TCF family and interacts with epigenetic and chromatin modifiers 13,14 . Song et al. reported a protein interaction between CTNNB1 and the DNA methyltransferase DNMT1 in cancer cells which stabilizes each protein and regulates downstream CTNNB1 and DNMT1 functions suggesting a cross-regulation between Wnt signalling and DNA methylation 15 . Changes in the DNA methylation pattern have been described in various solid tumours, including various mesenchymal neoplasms such as chondrosarcoma, Ewing sarcoma and rhabdomyosarcoma 16-21 . These distinct methylation patterns could be of diagnostic value and capable of discerning tumour subtypes, may yield clinically relevant biomarkers that can direct treatment choices, and can potentially reveal novel treatment opportunities 22-26 . 4