{"entity":{"id":"paper-seshagiri-rspo-fusions-colon-nature-2012","kind":"paper","name":"Recurrent R-spondin fusions in colon cancer","aka":[],"tldr":"Sequencing the DNA and the RNA of more than 70 colon tumours turned up a new way of switching on the growth signal that drives the disease: two genes fused so that an amplifier of the WNT pathway is overproduced, in tumours whose usual brake gene is intact.","summary":"More than 70 pairs of primary human colon tumours and matched normal tissue were analysed by exome, transcriptome and copy-number sequencing, identifying 36,303 protein-altering somatic changes. New recurrent mutations were found in the WNT pathway gene TCF7L2, in chromatin-remodelling genes including TET2 and TET3, and in receptor tyrosine kinases including ERBB3; 23 significantly mutated genes were identified, including ATM. Copy-number and RNA sequencing found amplification and corresponding overexpression of IGF2. Recurrent gene fusions involving RSPO2 and RSPO3 together occurred in 10% of the tumours, were mutually exclusive with APC mutation, and potentiated WNT signalling in functional assays.\n\nDeposited as coadread_genentech on cBioPortal (72 sequenced tumours).","asOf":"2026-09-24","links":[{"label":"Seshagiri et al., Nature 2012: recurrent R-spondin fusions in colon cancer (more than 70 tumour pairs)","url":"https://doi.org/10.1038/nature11282"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22895193/"},{"label":"cBioPortal study coadread_genentech (Genentech, Nature 2012; 72 sequenced colon tumours, the R-spondin fusion discovery set)","url":"https://www.cbioportal.org/study/summary?id=coadread_genentech"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["wes-wgs","rna-seq"],"targets":["rspo3","rspo2","tcf7l2","apc","atm"],"drugs":[],"companies":[],"institutions":[],"pathways":["wnt","rtk-activation"],"terms":["gene-fusion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2012,"doi":"10.1038/nature11282","pmid":"22895193","authors":"Seshagiri S, Stawiski EW, Durinck S, et al.","paperType":"translational","findings":["RSPO2 and RSPO3 fusions in 10% of colon tumours, mutually exclusive with APC mutation.","IGF2 amplification with matching overexpression.","New recurrent mutations in TCF7L2, TET2, TET3 and ERBB3."],"whatItMeans":"It gave the WNT pathway a second, druggable entry point: RSPO fusion tumours still need the upstream receptor complex, so they are the population porcupine and RSPO3 inhibitors are being tested in.","caveats":["Small discovery cohort; DNA panels find RSPO fusions far less often (0.4% in 7,237 MSK-IMPACT samples) because intron coverage is partial.","No approved therapy follows from an RSPO fusion."],"changedPractice":false,"participants":74},"route":"/key-papers/paper-seshagiri-rspo-fusions-colon-nature-2012/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"technology":[{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/"},{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"rspo2","kind":"target","name":"RSPO2","route":"/targets/rspo2/"},{"id":"rspo3","kind":"target","name":"RSPO3","route":"/targets/rspo3/"},{"id":"tcf7l2","kind":"target","name":"TCF7L2","route":"/targets/tcf7l2/"}],"pathway":[{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"term":[{"id":"gene-fusion","kind":"term","name":"Gene fusion","route":"/terms/gene-fusion/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}