Milea Timbergen

59 Introduction Sporadic desmoid-type fibromatosis (DTF) is a soft tissue tumour characterized by local invasive growth and unpredictable growth behaviour with phases of progression, stable disease and even spontaneous regression 1-4 . The incidence in the Dutch population is approximately five cases per million people per year 5 . Affected patients are mostly females, with a peak incidence between the second and fourth decade of life 6-9 . Sporadic DTF has a mesenchymal origin, arising in musculoaponeurotic structures and can develop at practically any location in the body 10 . The most common site is the abdominal wall whereas the predominant extra-abdominal sites are the trunk and the proximal part of the extremities 7, 11 . Treatment includes conservative management via active surveillance, surgical resection, radiotherapy or systemic therapy. The latter option comprises non- steroidal anti-inflammatory drugs (NSAIDs), anti-hormonal agents such as tamoxifen, low dose chemotherapy such as a combination of methotrexate with either vinblastine or vinorelbine, and tyrosine kinase inhibitors such as imatinib, sorafenib, or nilotinib 12 . No recommendations about the sequence of existing systemic treatment options can be given yet, although the recent results of a randomized phase 3 trial suggest a possible role of sorafenib in symptomatic patients 13 . Recurrence rates after treatment are high with a 5-year local recurrence rate of 49% after surgery 9 . The CTNNB1 (β-catenin) gene is mutated in the vast majority of sporadic DTF tumours 9, 14-22 . Normally, β-catenin acts as a key mediator in the Wingless (Wnt) signalling pathway by operating as a transcriptional activator through binding in the nucleus to members of the TCF/LEF transcription factor family. The CTNNB1 mutations, found in DTF, mainly affect two codons in exon 3; substituting threonine at position 41 with alanine (T41A) and replacing serine at position 45 with either phenylalanine (S45F) or proline (S45P) 8, 9 . These mutations prevent its phosphorylation, poly-ubiquitination and subsequent proteasomal degradation. Instead, β-catenin is stabilized and translocated into the nucleus where it drives transcription of Wnt target genes. The Wnt signalling cascade is involved in several biological processes like embryonic development and maintenance and regeneration of adult cells 23, 24 . The aberrant activation of the Wnt signalling pathway, as in DTF, is observed in various malignancies like colorectal cancer, breast cancer and non-small cell lung cancer, and is considered to be a driver of tumorigenesis 14, 25-28 . The CTNNB1 genotype-phenotype relation has been extensively investigated in liver cancer, providing evidence that different CTNNB1 mutations are linked to different levels of β-catenin activation. The S45 mutation leads to a weak activation and T41 mutations are associated with a moderate activation which may yield differences in clinical behaviour 29 . Desmoid tumours that harbor a S45F 3