Predicted functional consequences of WNT ligand mutations in colorectal cancer

Mutations to wingless integration site (WNT) ligands in cancer are poorly understood. WNT ligands are a family of secreted proteins that trigger the activation of the WNT pathway, with essential roles in cell development and carcinogenesis, particularly in the colorectal tract. While the structure of WNT ligands has been elucidated, little is known about how mutations in these proteins affect colorectal cancer. Here, we show that mutations in WNT ligands found in colorectal cancer show regional specificity and selectivity for particular conserved sequences. We further show that mutations in colorectal cancer are not selecting for changes in the binding affinity of the ligands to their receptor. We use clinical data to identify mutations to WNT5A as under selection and correlating with patient outcomes in colorectal cancer, and by combining mutational data and folding energy calculations, elastic network modeling, and molecular dynamics simulations, we show that these mutations alter its structural dynamics and flexibility. Thus, we predict a novel structure-function relationship for mutations in WNT ligands in human cancers.