# Recurrent R-spondin fusions in colon cancer

Source: https://onco.cc/key-papers/paper-seshagiri-rspo-fusions-colon-nature-2012/  
OnCo record `paper-seshagiri-rspo-fusions-colon-nature-2012` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

Deposited as coadread_genentech on cBioPortal (72 sequenced tumours).

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature
- Year: 2012
- DOI: 10.1038/nature11282
- Authors: Seshagiri S, Stawiski EW, Durinck S, et al.
- 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.
- What it means: 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.

## Sources

- Seshagiri et al., Nature 2012: recurrent R-spondin fusions in colon cancer (more than 70 tumour pairs): https://doi.org/10.1038/nature11282
- PubMed: https://pubmed.ncbi.nlm.nih.gov/22895193/
- cBioPortal study coadread_genentech (Genentech, Nature 2012; 72 sequenced colon tumours, the R-spondin fusion discovery set): https://www.cbioportal.org/study/summary?id=coadread_genentech

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [RNA sequencing & expression profiling](https://onco.cc/technologies/rna-seq/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [APC](https://onco.cc/targets/apc/), [ATM](https://onco.cc/targets/atm/), [HER2](https://onco.cc/targets/her2/), [RSPO2](https://onco.cc/targets/rspo2/), [RSPO3](https://onco.cc/targets/rspo3/), [TCF7L2](https://onco.cc/targets/tcf7l2/)
- pathways: [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/), [Wnt / β-catenin](https://onco.cc/pathways/wnt/)
- terms: [Gene fusion](https://onco.cc/terms/gene-fusion/)
- journals: [Nature](https://onco.cc/journals/nature/)

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