RT Journal Article
SR Electronic
T1 The most common RNF43 mutant G659Vfs41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 711382
DO 10.1101/711382
A1 Jianghua Tu
A1 Soohyun Park
A1 Wangsheng Yu
A1 Sheng Zhang
A1 Ling Wu
A1 Kendra Carmon
A1 Qingyun J. Liu
YR 2019
UL http://biorxiv.org/content/early/2019/07/22/711382.abstract
AB RNF43 is an E3 ligase that inhibits Wnt signaling by ubiquitinating Wnt receptors for degradation. It is mutated in various cancer types with the most recurrent mutation being the frameshift G659Vfs41 with frequencies of ~5-8% in colon, stomach and endometrial cancers. The mutation has always been assumed to be loss-of-function that would lead to increased Wnt signaling and tumorigenesis, yet no functional characterization has been reported. We analyzed the distribution of the G659Vfs41 mutation and its association with other cancer gene mutations, and found that the mutation occurred nearly exclusively in tumors with low expression of the DNA mismatch repair gene MLH1. Mutant RNF43-G659Vfs41 was no different from wild type RNF43 in expression, localization, R-spondin binding, promotion of Wnt receptor degradation, inhibition of Wnt signaling. We also found that colon tumors with RNF43-G659Vfs41 had low expression of Wnt/β-catenin signaling markers and were frequently mutated in BRAF. A colon cancer cell line with RNF43-G659Vfs41 and BRAF-V600E mutations was uniquely sensitively to activation of Wnt/β-catenin signaling. These findings indicate that RNF43-G659Vfs41 is likely a passenger mutation in MLH1-down regulated tumors, not a loss-of-function driver mutation that facilitates tumorigenesis. Tumors with RNF43-G659Vfs41 and BRAF-V600E may be susceptible to activators of Wnt signaling.