Abstract 5839: Exome sequencing revealed comparable frequencies of RNF43 mutations and BRAF mutations in Middle Eastern colorectal cancer

Abstract Mutation-induced activation of Wnt-β Catenin signaling is a frequent event in CRC. The E3 ubiquitin ligase, RNF43, has been reported to negatively regulate the Wnt signaling pathway. Although, RNF43 mutations are frequently seen in CRC, its role in CRC from Middle Eastern ethnicity remains unclear. Therefore, we conducted this study to assess the frequency of RNF43 mutations, the clinico-pathological and molecular associations in two independent cohorts of Middle Eastern CRC. Exome sequencing was utilized to identify the somatic mutations in RNF43 gene and in known CRC driver genes including APC, TP53, KRAS, BRAF and NRAS among 113 CRC cases of discovery cohort. In validation cohort of 107 CRC cases, Sanger sequencing was employed to detect the mutations in exon 2, 4, 8 and 9 in RNF43 gene while Targeted capture sequencing was conducted to identify the mutations in entire region of APC gene and hotspot regions of KRAS, BRAF, NRAS and TP53 genes. RNF43 somatic mutations were found in 5.9% (13/220) of the entire CRC cohort, which is similar in frequency to BRAF mutations, which were identified in 3.6% (8/220). The mutations in other known driver genes including APC, TP53, KRAS and NRAS were observed in 58.2% (128/220), 50.9% (112/220), 46.4% (102/220) and 2.7% (6/220) cases, respectively, in all 220 tumors examined. However, no significant association between RNF43 mutations and BRAF mutations was seen. RNF43 was found to be inversely correlated to APC and TP53 mutations. Clinico-pathological analysis showed a strong association of RNF43 mutations with right sided and sporadic deficient mismatch repair (dMMR) CRC. No association was identified between RNF43 mutation and other clinico-pathological features such as age, tumor histological subtype, tumor grade or patients’ prognosis. Multivariate logistic regression analysis revealed that dMMR status (Odds ratio = 5.43; 95% confidence interval = 1.12 - 26.32; p = 0.0356) and wild type APC (Odds ratio = 4.77; 95% confidence interval = 1.51 - 19.77; p = 0.0312) were independent predictors of RNF43 mutation. Our results revealed that RNF43 mutations do occur in CRC from Middle Eastern ethnicity at comparable frequencies with BRAF mutations and represent a distinct molecular subtype which further enhance 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. Citation Format: Rong Bu, Abdul K. Siraj, Tariq Masoodi, Sandeep Kumar Parvathareddy, Kaleem Iqbal, Allianah D. Benito, Sarah Siraj, Nabil Siraj, Maha Al Rasheed, Saeeda O. Ahmed, Wael AL-Haqaw, Maria Angelita Sabido, Mark Ranier Diaz, Padmanaban Annaiyappanaidu, Khawla S. Al-Kuraya. Exome sequencing revealed comparable frequencies of RNF43 mutations and BRAF mutations in Middle Eastern colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5839.