Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma

J Pathol. 2016 Jun;239(2):133-8. doi: 10.1002/path.4709. Epub 2016 Apr 9.


The molecular mechanisms underlying the serrated pathway of colorectal tumourigenesis, particularly those related to traditional serrated adenomas (TSAs), are still poorly understood. In this study, we analysed genetic alterations in 188 colorectal polyps, including hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), TSAs, tubular adenomas, and tubulovillous adenomas by using targeted next-generation sequencing and reverse transcription-PCR. Our analyses showed that most TSAs (71%) contained genetic alterations in WNT pathway components. In particular, PTPRK-RSPO3 fusions (31%) and RNF43 mutations (24%) were frequently and almost exclusively observed in TSAs. Consistent with the WNT pathway activation, immunohistochemical analysis showed diffuse and focal nuclear accumulation of β-catenin in 53% and 30% of TSAs, respectively. APC mutations were observed in tubular and tubulovillous adenomas and in a subset of TSAs. BRAF mutations were exclusively and frequently encountered in serrated lesions. KRAS mutations were observed in all types of polyps, but were most commonly encountered in tubulovillous adenomas and TSAs. This study has demonstrated that TSAs frequently harbour genetic alterations that lead to WNT pathway activation, in addition to BRAF and KRAS mutations. In particular, PTPRK-RSPO3 fusions and RNF43 mutations were found to be characteristic genetic features of TSAs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: R-spondin; RNF43; WNT; large intestine; traditional serrated adenoma.

MeSH terms

  • Adenoma / genetics*
  • Adenoma / pathology
  • Aged
  • Cell Transformation, Neoplastic
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Female
  • Humans
  • Hyperplasia / genetics
  • Hyperplasia / pathology
  • Intestinal Polyps / genetics
  • Intestinal Polyps / pathology
  • Intestines / pathology
  • Male
  • Mutation
  • Oncogene Fusion
  • Oncogene Proteins / genetics*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / genetics*
  • Sequence Analysis, DNA
  • Thrombospondins / genetics*
  • Ubiquitin-Protein Ligases
  • Wnt Signaling Pathway / genetics*
  • beta Catenin / metabolism


  • DNA-Binding Proteins
  • Oncogene Proteins
  • RSPO3 protein, human
  • Thrombospondins
  • beta Catenin
  • RNF43 protein, human
  • Ubiquitin-Protein Ligases
  • PTPRK protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2