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

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.