Clonal cooperation in FAP adenomas and tumorigenesis
Research type
Research Study
Full title
Clonal cooperation as a mechanism of adenoma formation and tumour progression in FAP
IRAS ID
355317
Contact name
Benjamin Zare
Contact email
Sponsor organisation
London North West University Healthcare NHS Trust
Duration of Study in the UK
2 years, 0 months, 30 days
Research summary
Familial adenomatous polyposis (FAP) is an inherited disorder caused by a pathogenic variant adenomatous polyposis coli (APC).(1) It results in multiple adenomatous polyps in the colon and wider gastrointestinal (GI) tract, and, without treatment, the risk of developing colorectal cancer (CRC) from these adenomas approaches 100% at a median age of 35–45 years(2), the risk of other GI tract malignancies (e.g., stomach, duodenal, etc.) notwithstanding. The human colon consists of columnar epithelial cells, which form finger-like infoldings that are the basic functional units of the intestine – crypts.(3) APC loss within crypts has been shown to lead to adenoma formation, manifesting as fields of mutant crypts.(4) Multiple mutant crypts are required to form adenomas, prompting the question whether they change their local environment to form a polyclonal adenoma – a theory known as ‘clonal cooperation’. Although polyclonality has been confirmed in FAP adenomas, we have yet to understand how this arises at a molecular level.
In mice, upon APC loss, mutant clones appear to be rapidly detected, and trapped in small collagen capsules produced by the local microenvironment, which has led to a hypothesized mechanism of adenoma formation that, if multiple of these trapped mutant clones are in proximity, then they may be able to secrete enough matrix metalloproteinase (MMP) chemicals to break through the aforementioned capsule, and thus grow and coalesce together. If we can demonstrate this phenomenon in human tissue, and assess whether polyclonality is in fact a universal intermediate step in tumour progression (across the entire gastrointestinal tract), we may be one step closer to finding targets for adenoma treatment and prevention in FAP.
Therefore, we will conduct molecular profiling (based on immunohistochemical and in-situ hybridization techniques) in samples – polyp/cancer/precancerous samples – historically collected from patients with FAP, with the aim of identifying this process in humans.References:
1. Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009;4(1):1–23.
2. Bussey HJR. Familial Polyposis Coli. Family Studies, Histopathology, Differential Diagnosis, and Results of Treatment. Vol. 13, Journal of Medical Genetics. 1976. p. 415–6.
3. Humphries A, Wright NA. Colonic crypt organization and tumorigenesis. Nat Rev Cancer. 2008;8(6):415–24.
4. Fischer JM, Schepers AG, Clevers H, Shibata D, Liskay RM. Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention. Carcinogenesis. 2014;35(1):237–46.REC name
North West - Greater Manchester West Research Ethics Committee
REC reference
25/NW/0346
Date of REC Opinion
8 Dec 2025
REC opinion
Further Information Favourable Opinion