Molecular characterisation of desmoid disease in FAP
Research type
Research Study
Full title
Molecular characterisation of desmoid disease in familial adenomatous polyposis
IRAS ID
338903
Contact name
Andrew Latchford
Contact email
Sponsor organisation
London North West University Healthcare NHS Trust
Clinicaltrials.gov Identifier
N/A, N/A
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
Familial adenomatous polyposis (FAP) is an inherited disorder caused by a pathogenic variant in the adenomatous polyposis coli (APC) gene, with an incidence of 1 per 8300 births, equally affecting both sexes. Extra-colonic manifestations of FAP are the cause of death in the majority of patients – the most challenging are desmoids, benign myofibroblastic proliferations that can cause major morbidity and mortality. Whilst not metastasizing, desmoids are often infiltrative or locally aggressive and invasive, penetrating organs, compressing vessels and nerves, eroding bones, invading muscle, and causing bowel/ureteric obstruction. They can arise sporadically or in association with FAP, with desmoids 850-1000 times commoner in FAP sufferers than in general.
APC is a tumour suppressor gene, with loss of function occurring when pathogenic variants occur in both alleles (based on Knudson’s “two-hit” hypothesis). It is the site of most pathogenic variants causing both adenomas and desmoids, in FAP.9 In desmoid pathogenesis, disruption of Wnt/beta-catenin signalling is a common pathway – most sporadic desmoids occur from somatic pathogenic variants of the beta-catenin gene (CTNNB1), and FAP-associated desmoids from alterations in the APC gene. Both result in a truncated APC protein, less able to degrade beta-catenin, so this accumulates resulting in translocation to the nucleus, and upregulation of transcription of genes involved in tumorigenesis.
With recurrence rates over 40%, surgery is no longer considered standard of care for desmoids, and surveillance alongside potential systemic agents is advised for initial management. However, the genetic profile of FAP-associated desmoids is poorly-characterised, and lack of knowledge of their biology makes it difficult to stratify who would benefit from surgery, systemic treatments, or even chemoprophylaxis.
Therefore, we will conduct comprehensive molecular profiling analyses (based on multiplex sequencing and next-generation RNA sequencing), with the aim of identifying biomarkers predictive of prognosis post-operatively alongside potential targets for drug therapy and chemoprevention.REC name
West Midlands - Solihull Research Ethics Committee
REC reference
24/WM/0070
Date of REC Opinion
2 Apr 2024
REC opinion
Further Information Favourable Opinion