RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis

Bond, Catherine E., McKeone, Diane M., Kalimutho, Murugan, Bettington, Mark L., Pearson, Sally-Ann, Dumenil, Troy D., Wockner, Leesa F., Burge, Matthew, Leggett, Barbara A. and Whitehall, Vicki L. J. (2016) RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis. Oncotarget, 7 43: 70589-70600. doi:10.18632/oncotarget.12130


Author Bond, Catherine E.
McKeone, Diane M.
Kalimutho, Murugan
Bettington, Mark L.
Pearson, Sally-Ann
Dumenil, Troy D.
Wockner, Leesa F.
Burge, Matthew
Leggett, Barbara A.
Whitehall, Vicki L. J.
Title RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis
Formatted title
RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis
Journal name Oncotarget   Check publisher's open access policy
ISSN 1949-2553
Publication date 2016-09-20
Sub-type Article (original research)
DOI 10.18632/oncotarget.12130
Open Access Status DOI
Volume 7
Issue 43
Start page 70589
End page 70600
Total pages 12
Place of publication Albany, NY, United States
Publisher Impact Journals LLC
Language eng
Subject 2730 Oncology
Abstract 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.
Formatted abstract
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.
Keyword BRAF
Colorectal cancer
MSI
RNF43
Wnt signalling
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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Sub-type: Article (original research)
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