BACKGROUND Colorectal cancer(CRC)is the second leading cause of cancer-related death,lar-gely due to limited treatment options in advanced stages.Genomic alterations in advanced CRC(aCRC)are complex and not fully char...BACKGROUND Colorectal cancer(CRC)is the second leading cause of cancer-related death,lar-gely 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 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.展开更多
文摘BACKGROUND Colorectal cancer(CRC)is the second leading cause of cancer-related death,lar-gely 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 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.
