Familial Adenomatous Polyposis and Associated Carcinogenesis

Familial adenomatous polyposis (FAP) arises from inherited mutations in the APC tumour suppressor gene and is characterised by the development of hundreds to thousands of adenomatous polyps throughout the colon and rectum, often beginning in adolescence. In the absence of surgical intervention, one or more polyps progress through stages of dysplasia to invasive colorectal carcinoma, typically by early middle age. Beyond the colorectum, FAP confers elevated risks of neoplasms in the duodenum, stomach, pancreas, thyroid and biliary tract, as well as desmoid tumours. Prophylactic colectomy substantially reduces colorectal cancer incidence but necessitates vigilant endoscopic surveillance of the remaining gastrointestinal tract and management of extraintestinal manifestations. At the molecular level, aberrant Wnt–β-catenin signalling, chronic inflammatory signalling, extracellular matrix remodelling and metabolic reprogramming orchestrate the transition from benign polyp to carcinoma. Consequently, chemopreventive interventions targeting cyclo-oxygenase pathways, polyamine metabolism and mTOR signalling are under active clinical and preclinical investigation.

Research from Nature Portfolio

Recent multiomic investigations have integrated transcriptomic, proteomic, metabolomic and lipidomic data from normal mucosa, benign adenomas and dysplastic polyps in FAP patients to delineate the earliest events in colorectal tumourigenesis. This approach revealed temporal activation of inflammatory mediators, notably the arachidonic acid pathway, shifts in amino acid and lipid metabolism, and dynamic changes in extracellular matrix composition. The identification of early engagement of these pathways supports the therapeutic potential of non-steroidal anti-inflammatory drugs and metabolic inhibitors as prophylactic strategies in high-risk populations.

Familial Adenomatous Polyposis and Associated Carcinogenesis publication trend

The graph below shows the total number of articles in familial adenomatous polyposis and associated carcinogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Familial Adenomatous Polyposis (FAP): An autosomal dominant syndrome caused by germline APC mutations, leading to widespread colorectal adenoma formation.

Adenomatous Polyposis Coli (APC) gene: A key tumour suppressor whose loss of function triggers aberrant Wnt signalling and polyp development.

Dysplasia: A precancerous histopathological state marked by abnormal cell architecture and atypical proliferation.

Prophylactic colectomy: Elective surgical removal of the colon to prevent malignant transformation of adenomatous polyps in FAP.

Multiomic profiling: Integrated analysis of multiple molecular layers (e.g. transcriptome, proteome, metabolome) to comprehensively characterise biological processes.

Chemoprevention: Use of pharmaceutical agents to inhibit, delay or reverse the process of carcinogenesis in susceptible individuals.

References

1. Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis. Nature Cancer (2024).
2. Cancer in Patients With Familial Adenomatous Polyposis: A Nationwide Danish Cohort Study With Matched Controls. Gastroenterology (2023).
3. Risk of gastric adenoma and adenocarcinoma in patients with familial adenomatous polyposis in Japan: a nationwide multicenter study. Journal of Gastroenterology (2024).
4. Rapamycin Inhibition of Polyposis and Progression to Dysplasia in a Mouse Model. PLOS ONE (2014).
5. The Adenomatous Polyposis Coli Tumor Suppressor Gene Regulates Expression of Cyclooxygenase-2 by a Mechanism That Involves Retinoic Acid*. Journal of Biological Chemistry (2006).
6. Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial. BMC Gastroenterology (2016).
7. Management of familial adenomatous polyposis and MUTYH-associated polyposis; new insights. Best Practice & Research Clinical Gastroenterology (2022).