Tur R, Abad M, Filipovich E, Rivas MB, Rodriguez M, Montero JC, Sayagués JM. RSPO3 rearrangements in advanced colorectal cancer patients and their relationship with disease characteristics. World J Gastrointest Oncol 2025; 17(11): 112838 [DOI: 10.4251/wjgo.v17.i11.112838]
Corresponding Author of This Article
José María Sayagués, PhD, Senior Scientist, Department of Pathology-University Hospital of Salamanca, Institute of Biomedical Research of Salamanca, Paseo de San Vicente, 58-182, Salamanca 37007, Spain. ppmari@usal.es
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Nov 15, 2025 (publication date) through Nov 13, 2025
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World Journal of Gastrointestinal Oncology
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Tur R, Abad M, Filipovich E, Rivas MB, Rodriguez M, Montero JC, Sayagués JM. RSPO3 rearrangements in advanced colorectal cancer patients and their relationship with disease characteristics. World J Gastrointest Oncol 2025; 17(11): 112838 [DOI: 10.4251/wjgo.v17.i11.112838]
World J Gastrointest Oncol. Nov 15, 2025; 17(11): 112838 Published online Nov 15, 2025. doi: 10.4251/wjgo.v17.i11.112838
RSPO3 rearrangements in advanced colorectal cancer patients and their relationship with disease characteristics
Raquel Tur, Mar Abad, Elena Filipovich, Maria Belen Rivas, Marta Rodriguez, Juan Carlos Montero, José María Sayagués
Raquel Tur, Department of Pathology, Hospital Nuestra Señora de Sonsoles, Avila 05004, Spain
Mar Abad, Maria Belen Rivas, Marta Rodriguez, Juan Carlos Montero, José María Sayagués, Department of Pathology-University Hospital of Salamanca, Institute of Biomedical Research of Salamanca, Salamanca 37007, Spain
Mar Abad, Marta Rodriguez, José María Sayagués, Department of Cell Biology and Pathology, University of Salamanca, Salamanca 37007, Spain
Elena Filipovich, Department of Oncology, Hospital Nuestra Señora de Sonsoles, Avila 05004, Spain
Juan Carlos Montero, José María Sayagués, Centro de Investigación Biomédica en Red Cáncer, Madrid 28029, Spain
Co-first authors: Raquel Tur and Mar Abad.
Co-corresponding authors: Juan Carlos Montero and José María Sayagués.
Author contributions: Tur R and Abad M contributed equally to this work as co-first authors; Abad M, Tur R, Montero JC, and Sayagués JM designed and analyzed the study; Tur R, Rivas MB, Filipovich E, and Abad M performed the experiments; Tur R, Abad M, Rodriguez M, and Filipovich E contributed to data collection; Abad M and Rodriguez M contributed to funding acquisition; Montero JC and Sayagués JM coordinated the study, wrote the manuscript, and performed the critical revision of the article; Montero JC and Sayagués JM contributed equally to this work as co-corresponding authors and should be considered as senior last authors. All authors have read and approved the final manuscript.
Institutional review board statement: This study was approved by the Ethics Committee of the University Hospital of Avila, No. 2024 05 1657.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data generated in the present study may be found in the Zenodo database under accession number 16750586 or at the following URL: https://zenodo.org/uploads/16750586. All other data generated in the present study may be requested from the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: José María Sayagués, PhD, Senior Scientist, Department of Pathology-University Hospital of Salamanca, Institute of Biomedical Research of Salamanca, Paseo de San Vicente, 58-182, Salamanca 37007, Spain. ppmari@usal.es
Received: August 7, 2025 Revised: September 19, 2025 Accepted: October 27, 2025 Published online: November 15, 2025 Processing time: 99 Days and 6 Hours
Abstract
BACKGROUND
Colorectal cancer (CRC) is the second leading cause of cancer-related death, largely due to limited treatment options in advanced stages. Genomic alterations in advanced CRC (aCRC) are complex and not fully characterized, with only 30% of patients benefiting from targeted therapies.
AIM
To investigate the molecular heterogeneity of primary aCRC in order to identify clinically relevant genomic alterations.
METHODS
We conducted a retrospective molecular analysis of 73 consecutive patients with histologically confirmed primary aCRC (stage pT4a-b). All molecular findings were correlated with available clinicopathological data. In addition, we performed survival analyses using publicly available datasets and tools.
RESULTS
Genetic abnormalities identified in primary tumors were most frequently mutations in tumor protein p53 (58% of cases), Kirsten rat sarcoma viral oncogene homolog (52%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (25%), B-Raf kinase (11%) and fibroblast growth factor receptor 3 (8%), as well as R-spondin 3 (RSPO3) fusions (8%). Alterations in the tumor protein p53 and neuroblastoma RAS viral oncogene homolog genes were predominantly observed in tumors from the left colon, whereas B-Raf kinase mutations and RSPO3 fusions were more frequently detected in the right or transverse colon. We also show a strong association between the presence of RSPO3 rearrangements and patients with small tumors, normal carcinoembryonic antigen levels, and microsatellite stable tumors. Furthermore, aCRC patients with protein tyrosine phosphatase receptor type k::RSPO3 fusions exhibited a higher mortality rate. Elevated RSPO3 gene expression levels were also significantly correlated with poorer OS across two large, independent CRC cohorts.
CONCLUSION
This study identifies a relatively high incidence of RSPO3 rearrangements in aCRC and a strong association with clinical features. Furthermore, we find that RSPO3 fusions are associated with poorer OS.
Core Tip: In our study, we identified key genomic alterations in advanced colorectal cancer using next-generation sequencing. The most frequent mutations occurred in tumor protein p53, Kirsten rat sarcoma viral oncogene homolog, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, B-Raf kinase, and fibroblast growth factor receptor 3, with distinct mutational patterns observed between tumors originating in the left and right colon. Notably, protein tyrosine phosphatase receptor type k::R-spondin 3 fusion were detected in 8% of cases, predominantly in right-sided tumors, and were associated with poorer overall survival, supporting their relevance as both a biomarker and therapeutic target. Larger prospective studies are needed to confirm their clinical utility in colorectal cancer.
