RSPO3 rearrangements in advanced colorectal cancer patients and their relationship with disease characteristics

Abstract

[EN]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.

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 [PMID: 41281482 DOI: 10.4251/wjgo.v17.i11.112838]