Frameshift mutation of UVRAG: Switching a tumor suppressor to an oncogene in colorectal cancer

Abstract

Colorectal cancer (CRC) ranks as the second leading cause of cancerrelated deaths in the Western world. It has a nearly 50% metastasis rate and only a subset of patients respond to current treatment strategy. UVRAG, a key autophagy effector and a guardian of chromosomal stability, is truncated by a frameshift (FS) mutation in CRC with microsatellite instability (MSI). However, the pathological and clinical significance of this UVRAG truncation remains less understood. Our recent study discovered that this FS mutation yields a much shortened form of the UVRAG protein, which counteracts most of the tumorsuppressor functions of wild-type (WT) UVRAG in autophagy, centrosome stability, and DNA repair in a dominantnegative fashion. Whereas this truncated mutation of UVRAG promotes tumorigenesis, epithelial-to-mesenchymal transition, and metastasis, it appears to sensitize CRC tumors to adjuvant chemotherapy, making it a potential molecular marker to individualize therapeutic approach in CRC.