RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis
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Catherine E. Bond1, Diane M. McKeone1, Murugan Kalimutho2, Mark L. Bettington1,3,4, Sally-Ann Pearson1, Troy D. Dumenil1, Leesa F. Wockner5, Matthew Burge6, Barbara A. Leggett1,4,7, Vicki L.J. Whitehall1,4,8
1Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
2Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
3Envoi Specialist Pathologists, Brisbane, Queensland, Australia
4School of Medicine, University of Queensland, Brisbane, Queensland, Australia
5Cancer and Population Studies, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
6Department of Oncology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
7Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
8Pathology Queensland, Brisbane, Queensland, Australia
Catherine E. Bond, email: Catherine.Bond@qimrberghofer.edu.au
Keywords: RNF43, colorectal cancer, BRAF, MSI, Wnt signalling
Received: April 07, 2016 Accepted: September 02, 2016 Published: September 20, 2016
Serrated pathway colorectal cancers (CRCs) are characterised by a BRAF mutation and half display microsatellite instability (MSI). The Wnt pathway is commonly upregulated in conventional CRC through APC mutation. By contrast, serrated cancers do not mutate APC. We investigated mutation of the ubiquitin ligases RNF43 and ZNRF3 as alternate mechanism of altering the Wnt signal in serrated colorectal neoplasia. RNF43 was mutated in 47/54(87%) BRAF mutant/MSI and 8/33(24%) BRAF mutant/microsatellite stable cancers compared to only 3/79(4%) BRAF wildtype cancers (p<0.0001). ZNRF3 was mutated in 16/54(30%) BRAF mutant/MSI and 5/33(15%) BRAF mutant/microsatellite stable compared to 0/27 BRAF wild type cancers (p=0.004). An RNF43 frameshift mutation (X659fs) occurred in 80% BRAF mutant/MSI cancers. This high rate was verified in a second series of 25/35(71%) BRAF mutant/MSI cancers. RNF43 and ZNRF3 had lower transcript expression in BRAF mutant compared to BRAF wildtype cancers and less cytoplasmic protein expression in BRAF mutant/MSI compared to other subtypes. Treatment with a porcupine inhibitor reduced RNF43/ZNRF3 mutant colony growth by 50% and synergised with a MEK inhibitor to dramatically reduce growth. This study suggests inactivation of RNF43 and ZNRF3 is important in serrated tumorigenesis and has identified a potential therapeutic strategy for this cancer subtype.
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