Clinical and cellular studies in the pathogenesis of desmoid tumours in familial adenomatous polyposis (FAP)

Abstract

Desmoid tumours are rare, myofibroblastic, soft tissue tumours. However, in the context of familial adenomatous polyposis, they can affect up to a quarter of patients. Desmoid tumours remain the most significant extra-intestinal manifestation of this cancer predisposing, autosomal dominant, condition. Due to their rarity, and unusual growth behaviour, studying these tumours remains a challenge. The clinical studies in this thesis aimed to highlight the complications associated with desmoid tumours and their impact on patient quality of life. The laboratory studies sought to identify potential pathways involved in their growth and detect genetic variants that may influence this process.

A retrospective cohort study identified a 25% risk of ureteric compression associated with intra-abdominal desmoid (IAD) tumours and supported a role for long-term urinary tract ultrasound surveillance. Small bowel transplant for complicated IAD disease has become part of the treatment pathway and was found to be a viable treatment option for complex cases. A quality of life study survey involving 70 people with FAP (32 with desmoid) identified a reduced quality of life associated with desmoid. This was mostly attributable to pain limiting physical and social activities. Histological analysis supported activation of the non-canonical Wnt pathway in desmoid tumours. This was a novel finding that could offer pathway targets for future research. Cell culturing of desmoids was largely unsuccessful and led to the initial development of a three-dimensional cell culture scaffold. This could improve future prospects of developing a successful desmoid cell line. Next generation sequencing of desmoid germline and tumour DNA identified several potential genes of interest. An upregulation of miRNA-34a-5p was detected in the serum of patients with desmoid and was also identified in tumour tissue. This could lead to future development of a circulating desmoid biomarker, whilst offering further pathways to explore for future research.