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Case Reports
. 2025 Aug 30;16(4):1749-1755.
doi: 10.21037/jgo-2025-77. Epub 2025 Aug 20.

A germline variant of ring finger protein 43 in an early onset, treatment-resistant metastatic gastric cancer: a case report

Benjamín García-Bloj  1 , Santiago Farah Celis  1 , Natalia Eva Orellana  1 , Tomás de Mayo Glasser  1 , Mauricio A Sáez  2 , Ignacio N Retamal  1 , Matías Muñoz-Medel  1 , Carolina Sánchez  1 , Felipe Pinto  1 , Paola Aravena  1 , Cristopher San Martín  1 , Andrea C Sabioncello H  1 , Marcelo Garrido Villanueva  1   3 , Fernando Sigler Chávez  1 , Juvenal A Ríos Leal  4 , Patricio A Manque  1   5 , José M Erpel  1 , Juan A Godoy  1 , Marcelo Garrido  1
Affiliations
Case Reports

A germline variant of ring finger protein 43 in an early onset, treatment-resistant metastatic gastric cancer: a case report

Benjamín García-Bloj et al. J Gastrointest Oncol. .

Abstract

Background: Ring finger protein 43 (RNF43) is an E3 ubiquitin-protein ligase that functions as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination, endocytosis, and subsequent degradation of Frizzled receptors within the Wnt receptor complex. It exerts its effects on both canonical and non-canonical Wnt signaling pathways.

Case description: This case report describes a 49-year-old female patient with a significant family history of cancer and parental consanguinity who was diagnosed with treatment-resistant stage IV gastric adenocarcinoma. Genomic profiling conducted via liquid biopsy identified a missense variant in RNF43 exon 9 (NM_017763.6, c.1948C>T; Arg650Ter) with a high variant allele frequency (VAF) of 49.5%. Confirmation of the R650* variant at the germline level underscores its clinical significance in early onset gastric cancer (GC) pathogenesis.

Conclusions: While interpretations of its pathogenicity vary in the ClinVar database, the application of the American College of Medical Genetics (ACMG) criteria suggests its potential involvement in cancer pathogenesis. This report highlights the necessity for further research to elucidate the role and impact of RNF43 in GC progression and develop specific preventive measures for affected families as genetic testing and counseling in high-risk families.

Keywords: Ring finger protein 43 (RNF43); case report; early-onset; gastric cancer (GC); germline variant.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-77/coif). I.N.R. reports FONDECYT grant (No. 11220563) from Chilean Government. M.G. reports receiving FONDECYT grant (No. 1221499) from Chilean Goverment; serving as Principal Investigator in clinical trials of MSD, BMS, Novartis, Roche, Astellas, Deciphera, PPD, IQVIA, Bayer, Principia, Covance, Daiichi-Sankyo, Basilea, PRA-Exelisis, Syneos, Zimeworks; serving on Scientific Advisory Board for Bayer, Novartis, MSD, BMS, Pfizer, Macrogenic, Merck; Teaching/Speaker Bureau Activities in Novartis, Pfizer, Bayer, BMS,MSD, GBT Biotoscana, Lilly; serving as Member of Societies and collaborative groups: ASCO, ESMO, ENETS, IGCS, SLAGO, SCOM, GOCCHI, Horizon 2020, GCCG and PanCancer; and President of GLOD. Grupo Latinoamericano de Oncología Digestiva. The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
RNF43 R650* variant in early onset gastric cancer. The RNF43 wild-type protein full three-dimensional structure, as predicted by the AlphaFold Protein Structure Database (ebi.ac.uk), is presented. The arginine residue (ARG 650) is depicted in the left panel (green). The RNF43 protein three-dimensional structure (balls and stick model) is illustrated, featuring a magnified view of the ARG 650 residue, shown in the same color (right panel). The RNF43 isoform-1 full amino acid canonical sequence (comprising 783 amino acids) is displayed, with the ARG 650 residue highlighted (red box) and the location of the stop signal indicated (inferior panel). [Sequence obtained from UniProt, RNF43-E3 ubiquitin-protein ligase RNF43-Homo sapiens (Human)|UniProtKB|UniProt] (12,13). RNF43, ring finger protein 43.
Figure 2
Figure 2
Family pedigree of a 49-year-old woman with an RNF43 germline variant. Pedigree analysis of the family revealed substantial consanguinity and a high prevalence of cancer among family members. Genetic analysis identified the same RNF43 germline variant (sig+) in one offspring, indicating its transmission within the family lineage. DOB, date of birth; LGL, living generation label; RNF43, ring finger protein 43.
See this image and copyright information in PMC

References

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