The paradox of AMER1 driver mutations in colorectal cancer

Primary Supervisor: Professor Ian Tomlinson

Second Supervisor: Dr Shamir Montazid

Project Overview

Cancer develops in part owing to somatic mutations acquired by so-called driver genes. About 90% of colorectal cancers are caused by mutations in the classical tumour suppressor gene, APC. These mutations are thought to lead to constitutive activation of the Wnt signalling pathway, leading to cell proliferation and stem-like properties. Another Wnt pathway driver gene inactivated in 10-15% of colorectal cancers is called AMER1, meaning APC MEmbrane Recruitment protein 1. AMER1 mutations almost never occur in the absence of APC mutations, yet a simple analysis would suggest that AMER1 mutations are redundant in the presence of mutated APC and so should not be found in human colorectal tumours. Even more confusingly, germline APC mutatiosn predispose to colorectal cancer, whereas germline AMER1 mutations cause the very rare human disease of osteopathia striata with cranial sclerosis. This project uses cancer 'omics data, animal models and intestinal organoids with the aim of explaining how somatic AMER1 mutations help a cell become cancerous, and whether AMER1 is only important on a background of APC mutation. Understanding what AMER1 mutation adds to APC mutation will provide important insights into why colorectal tumours grow and may suggest strategies to prevent or treat these clinically important malignancies.

Training Opportunities:

Training will be provided in human cancer genetics and multiomic analysis, animal and cell models of cancer, basic tissue morphology, and bioinformatic/statistical analysis of 'omic data.

Relevant Publications 

Tanneberger, K., Pfister, A.S., Kriz, V., Bryja, V., Schambony, A. and Behrens, J., 2011. Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1). Journal of Biological Chemistry, 286(22), pp.19204-19214.

Castro-Giner, F., Ratcliffe, P. and Tomlinson, I., 2015. The mini-driver model of polygenic cancer evolution. Nature Reviews Cancer, 15(11), pp.680-685.

van Ginkel, J., Tomlinson, I. and Soriano, I., 2023. The evolutionary landscape of colorectal tumorigenesis: recent paradigms, models, and hypotheses. Gastroenterology, 164(5), pp.841-846.