Exome sequencing revealed comparable frequencies of RNF43 and BRAF mutations in Middle Eastern colorectal cancer

Abstract

Mutation-induced activation of Wnt-β Catenin signaling pathway is frequent in CRC. The E3 ubiquitin ligase, RNF43, has been reported to negatively regulate the Wnt signaling pathway and RNF43 mutations are frequently seen in CRC. However, its role in Middle Eastern CRC remains unclear. Therefore, we employed Exome and Sanger sequencing technology to assess the frequency of RNF43 mutations and its association with other clinico-pathological features in Middle Eastern CRC. RNF43 mutations were found in 5.9% (13/220) of CRC cases and was inversely correlated to APC and TP53 mutations. A strong association of RNF43 mutations with right sided and sporadic microsatellite instable (MSI) CRC was observed. No association was identified between RNF43 mutation and other clinico-pathological features including BRAF mutation, age, tumor histological subtype, tumor grade or patients’ prognosis. Multivariate logistic regression analysis revealed that MSI status and wild type APC were independent predictor of RNF43 mutation. We conclude that RNF43 mutations occur in Middle Eastern CRC at comparable frequencies with BRAF mutations and represent a distinct molecular subtype which further enhances our understanding of how different mutational subsets of Wnt tumor suppressor genes link to distinct tumor characteristics, which might be considered for treatment strategies for CRC patients.

Ring Finger 43 Hot-spot Frameshift Mutation G659V in Colorectal Cancer Patients: Report from a Tertiary Cancer Care Hospital in North India

“…A loss of MMR proteins introduces replication errors, mostly in the microsatellites region. [ 15 19 20 ] The seven G tandem repeats involving codon 659 of the RNF43 gene make this region highly error-prone and more reliant on proficient MMR protein functioning, and so, as anticipated, we observed a greater frequency of the p.G659fs alteration in tumors showing loss in MMR protein staining. In our study, a co-loss of MLH1 and PMS2 was observed in two of the four patients harboring the p.G659fs variant.…”

“…Previous studies have associated RNF43 p.G659fs mutations with right-sided CRC and an aggressive phenotype. [ 19 22 23 ] In our study, three of the four mutant cases had right-side tumor location and favorable survival outcomes. Ethnic disparities and differences in the patient inclusion criteria, as well as the small sample size of our study, could be possible reasons for these discrepancies in results.…”

“…[ 6 10 ] The mutation was enriched in MMR-deficient tumors, which is consistent with previous reports that show a strong association between microsatellite instability and the RNF43 p.G659fs mutation. [ 6 13 19 ] MMR proteins are nuclear enzymes that correct mismatched bases that arise during replication in proliferating cells by binding to the incorrect base and facilitating its removal. A loss of MMR proteins introduces replication errors, mostly in the microsatellites region.…”

“…Our results are in agreement with former immunohistochemistry-based studies by Siraj et al ., and Elez et al ., which reported no correlation between nuclear β-catenin expression levels and the RNF43 p.G659fs mutation. [ 19 24 ] A functional study by Tu et al . further confirms that the RNF43 p.G659fs truncating variant is able to inhibit canonical Wnt signaling completely.…”

A new prognostic signature of 11 E3-related genes for colon cancer related to the immune microenvironment and somatic mutation

“…UPS dysregulation due to E3-related genes (E3RGs) mutations is strongly associated with poor cancer survival (Seeler and Dejean, 2017). In Colon Cancer pathogenesis, emerging studies have found the critical role of E3-related proteins, such as ZNF280A (Tian et al, 2022, 14), TMEM100 (Zheng et al, 2022), RNF43 (Schatoff et al, 2017;Siraj et al, 2022), and TRIM52 (Guo et al, 2022). Additionally the E3 ligases, RNF128 (Zhuang et al, 2022, 128) and TRIM29 (Jiang et al, 2021) have been reported in the regulation of PI3K/Akt pathway in colorectal cancer.…”