Here, we describe the first application of transgenic and inducible CRISPR/Cas9 technology to investigate cancer-associated chromosome rearrangements in vivo, and show that endogenous PTPRK–RSPO3 and EIF3E–RSPO2 rearrangements are sufficient to initiate hyperproliferation and tumour development in the intestine. This evidence concerns the gene RSPO3 and neoplasm.