RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer

Abstract

Right-sided colorectal cancer (RCRC) demonstrates worse survival outcome compared with left-sided CRC (LCRC). Recently, the importance of RNF43 mutation and BRAF V600E mutation has been reported in the serrated neoplasia pathway, which is one of the precancerous lesions in RCRC. It was hypothesized that the clinical significance of RNF43 mutation differs according to primary tumor sidedness. To test this hypothesis, the clinicopathological characteristics and survival outcome of patients with RNF43 mutation in RCRC and LCRC were investigated. Stage I-IV CRC patients (n=201) were analyzed. Genetic alterations including RNF43 using a 415-gene panel were investigated. Clinicopathological characteristics between RNF43 wild-type and RNF43 mutanttype were analyzed. Moreover, RNF43 mutant-type was classified according to primary tumor sidedness, i.e., rightsided RNF43 mutant-type or left-sided RNF43 mutant-type, and the clinicopathological characteristics between the two groups were compared. RNF43 mutational prevalence, spectrum and frequency between our cohort and TCGA samples were compared. RNF43 mutation was observed in 27 out of 201 patients (13%). Multivariate analysis revealed that age (≥65), absence of venous invasion, and BRAF V600E mutation were independently associated with RNF43 mutation. Among the 27 patients with RNF43 mutation, 12 patients were right-sided RNF43 mutant-type and 15 left-sided RNF43 mutant-type. Right-sided RNF43 mutant-type was significantly associated with histopathological grade 3, presence of lymphatic invasion, APC wild, BRAF V600E mutation, microsatellite instability-high (MSI-H), and RNF43 nonsense/ frameshift mutation compared with left-sided RNF43 mutanttype. Similarly, RNF43 nonsense/frameshift mutations were more frequently observed in RCRC compared with LCRC in the TCGA cohort (P=0.042). Right-sided RNF43 mutant-type exhibited significantly worse overall survival than RNF43 wild-type and left-sided RNF43 mutant-type (P=0.001 and P=0.023, respectively) in stage IV disease. RNF43 mutation may be a distinct molecular subtype which is associated with aggressive tumor biology along with BRAF V600E mutation in RCRC.

RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy

“…Notably, reduced RNF43 function is a negative prognosis factor in gastric cancer patients (Gao et al, 2017;Neumeyer et al, 2019a;Niu et al, 2015) and RNF43 loss of function type of mutation exacerbated Helicobacter pylori-induced gastric tumor carcinogenesis associated with the upregulation of WNT5A mRNA level (Katoh, 2007;Li et al, 2014;Neumeyer et al, 2019b;Peek and Crabtree, 2006). Further, in colorectal cancer RNF43 mutations were found to associate with BRAF V600E mutation (Matsumoto et al, 2020;Yan et al, 2017).These results suggest the existence of more universal functional WNT5A-RNF43 axis where RNF43 acts as a gatekeeper guarding the abnormal procancerogenic noncanonical Wnt pathway activation.…”

eVIP2: Expression-based variant impact phenotyping to predict the function of gene variants

“…RNF43 mutations are associated with microsatellite-instable tumors and are mutually exclusive with inactivating APC mutations [ 26 ]. Recurrent RNF43 mutations are predicted to create neopeptides [ 22 , 27 ] and have been associated with aggressive tumor biology [ 28 ]. The high frequency of the RNF43 G659fs variant suggested it could have a different functional impact than other truncating variants.…”

Post‐translational Wnt receptor regulation: Is the fog slowly clearing?

“…It has been observed that CRCs found in the right side of the colon show the MSI‐high phenotype, concentrated BRAF‐RNF43 mutations, and poor prognosis due to a lack of response to standard chemotherapy and the metastatic nature of the cancer cells, whereas CRCs in the left side have a better prognosis associated with the MSS phenotype and frequent APC‐KRAS mutations. [ 91–93 ] It is known that the right side of the colon (from the duodenum to two‐third of the transverse colon) originates from the midgut during embryogenesis, whereas the left side of the colon (from one‐third of the transverse colon to the anal canal) originates from the hindgut (Figure 3). [ 94 ] These facts suggest that the difference of gene mutation subsets between BRAF‐RNF43 and APC‐KRAS may be related to the different embryonic origins of the cells in these two regions.…”