Clinical and molecular characteristics of mutations as promising prognostic biomarkers in colorectal cancer

Autor: Zi-Yao Huang, Lei Wen, Liu-Fang Ye, Yu-Ting Lu, William Pat Fong, Ren-Jing Zhang, Si-Xian Wu, Zhi-Gang Chen, Yan-Yu Cai, Rui-Hua Xu, Yu-Hong Li, Zi-Ming Du, De-Shen Wang
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Therapeutic Advances in Medical Oncology, Vol 16 (2024)
Druh dokumentu: article
ISSN: 1758-8359
17588359
DOI: 10.1177/17588359231220600
Popis: Background: Transmembrane E3 ubiquitin ligase ( RNF43 ) mutations are present in approximately 6–18% of colorectal cancers (CRC) and could enhance Wnt/β-catenin signaling, which is emerging as a promising therapeutic target. This study aims to investigate the clinical and molecular characteristics and potential heterogeneity of RNF43 -mutant CRC. Methods: A total of 78 patients with RNF43 -mutant CRC were enrolled from July 2013 to November 2022. Demographic data, clinical characteristics, treatment regimens used, and survival outcomes were collected and analyzed. Results: Our study uncovered that patients with RNF43 mutations in the N-terminal domain (NTD; n = 50) exhibited shorter overall survival (OS; median months, 50.80 versus not reached; p = 0.043) compared to those in the C-terminal domain (CTD; n = 17). Most RNF43 mutations in NTD had positive primary lymph node status, low tumor mutation burden (TMB-L), and correlated with proficient mismatch repair (pMMR)/microsatellite stable (MSS) status. By contrast, RNF43 mutations in CTD were significantly enriched in deficient MMR (dMMR)/microsatellite instability (MSI-H) tumors with high TMB (TMB-H). N-terminal RNF43 -mutated tumors harbored a hotspot variant ( RNF43 R117fs ), which independently predicted a significantly worse outcome in pMMR/MSS CRC with a median OS of 18.9 months. Patients with RNF43 mutations and the BRAF V600E alterations demonstrated sensitivity to BRAF/EGFR inhibitors. Moreover, we observed that pMMR/MSS patients with RNF43 R117fs mutation had a higher incidence of stage IV, ⩾2 metastatic sites, low TMB, and none of them received PD-1/PD-L1 inhibitor therapy. Conclusion: Our findings provide the first evidence that RNF43 mutations in NTD and the R117fs variant correlate with a poorer prognosis in CRC patients, providing strategies for Wnt-targeted therapy to improve clinical efficacy.
Databáze: Directory of Open Access Journals
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