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Title: Chacterisation of desmoids in familial adenomatous polyposis
Author: Sinha, Ashish
ISNI:       0000 0004 2695 9340
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Desmoid tumours (DT) are rare myofibroblastic monoclonal proliferations, which are present in 10-25 per cent of patients with familial adenomatous polyposis (FAP). FAP desmoids are frequently intra-abdominal desmoids (IAD) or abdominal wall desmoids (AWD) and rarely can be extra-abdominal desmoids (EAD). DT are non-metastatic, locally invasive and display a variable clinical course. The aims of the studies in this thesis were to further characterize FAP associated desmoids and identify predictors of aggressive phenotype using clinical, radiological and cell culture model. A meta-analysis of 4,625 FAP patients with 559 (twelve per cent) DT identified a positive family history of DT (odds ratio (OR) 7.02 95%CI 4.15-11.9, p<0.0001), an APC mutation 3' to codon 1399 (OR4.37 95%CI 2.14-8.91, p<0.0001), previous abdominal surgery (OR3.35 95%CI 1.33-8.41, p=0.01) and female gender (OR1.57 95%CI 1.13-2.18, p=0.007) as risk factors for DT development. Analysis of 558 FAP patients with IAD in 49 (nine per cent) identified 3' APC mutation (hazards ratio (HR) 5.2 95%CI 2.1-13.3, p=0.001), positive family history (HR2.5 95%CI 1.4-4.6, p=0.003) and female gender (HR1.9 95%CI 1.0-3.5, p=0.04) to be predictive of IAD risk. Analysis 587 FAP patients revealed that twelve (two per cent) had a pre-operative AWD, EAD or both. The presence of pre-operative desmoids outside the abdomen predicted the development of IAD following laparotomy – relative risk (RR) 8.1 (95%CI 4.7-13.9, p<0.0001) for AWD and RR3.8 (95%CI 1.2-12.1, p=0.038) for EAD. A prospective comparative study of nine FAP patients found magnetic resonance imaging (MRI) to be superior to multi-detector computed tomography (MDCT) in the assessment of DT. MRI identified two lesions not seen on MDCT and gave better assessment of tumour enhancement. A cell culture model of FAP-DT cells was developed and characterised. DT cells displayed nuclear β-catenin immunopositivity confirming an upstream APC mutation. DT cells displayed cytoplasmic α-smooth muscle actin positivity confirming their myofibroblastic nature. In-vitro studies with proliferation markers Ki-67 and PCNA demonstrated that DT cells are immortal in culture. PCNA over-expression appeared to be predictive of aggressive desmoids.
Supervisor: Clark, Susan K. ; Phillips, Robin ; Tekkis, Paris Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral