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A novel class of oncogenic RNF43 mutations

Our publication describing how RNF43 mutations mediate a tumor suppressor-to-oncogene switch in cancer is now online at the EMBO Journal.

Our publication describing how RNF43 mutations mediate a tumor suppressor-to-oncogene switch in cancer is now online at the EMBO Journal. The full article can be found here.

A video summary of our findings can be found here.

Tumor suppressor genes play an essential role in preventing uncontrolled cell division and thereby prevent cancer initiation; similar to the brake in a car. According to the dogma, cancer mutations in such a tumor suppressor genes cause loss-of-function of the gene resulting in a dysfunctional brake leading to uncontrolled growth and cancer formation. However, mutations in genes often do not result in a complete loss of the encoded protein, but rather create a shorter truncated version of the protein. The role of which is often unclear.

We previously discovered that the tumor-suppressor RNF43 controls the growth of intestinal stem cells by performing a negative feedback role in the Wnt-signaling pathway. Mutations in RNF43 are found in a variety of cancer types, including colorectal, gastric, endometrial, and pancreatic cancer. Mutations that result in loss of RNF43 function, make cancer cells hypersensitive for inhibitors of the growth signal Wnt.

However, we discovered a completely new class of RNF43 mutations that result in a shorter truncated protein. Instead of loss-of-brake function, these mutations endow RNF43 with a novel oncogenic role. Oncogenic RNF43 mutations can activate the Wnt signaling pathway in a ligand-independent manner, similar to pressing the accelerator pedal in a car. We introduced these oncogenic RNF43 mutations in human colon organoids and found that these colon organoids became insensitive to Wnt inhibitors.

Our study, therefore, stresses the importance of understanding the oncogenic mechanisms of mutations that are found in cancer patients. This is important for improved patient stratification for applications of precision medicine

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