FrequentPTPRK-RSPO3fusions andRNF43mutations in colorectal traditional serrated adenoma

Abstract

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.

RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation

“…A concurrent study also reported frequent RNF43 mutation in serrated adenomas, along with PTPRK-RSPO3 fusion, although more in TSAs than SSAs 30. Since some of the SSAs we observed in both the familial and sporadic cases showed transitional morphology to TSA with focal development of villous configuration, they may represent a morphological continuum.…”

Rnf43

“…Sekine et al 16 used targeted next-generation sequencing and reverse transcriptase in a series of TSA and found that 24% showed RNF43 mutations.…”

Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer

“…Recent mouse studies using genetic techniques for cell-specific manipulation and cell lineage tracking have identified a population of intestinal stem cells called crypt base columnar cells (Barker et al, 2007) that can serve as the cell of origin of CRC (Barker et al, 2009). While intestinal stem cells are not the only cell capable of serving as the cell of origin (Visvader, 2011), they are by far the most efficient, requiring only a single activating mutation of the WNT/β-catenin pathway - a frequent event associated with the progression of the majority of CRCs, such as APC mutations in adenocarcinomas (Clevers and Nusse, 2012; Sekine et al, 2016). Paradoxically, despite a high prevalence among colorectal tumors, ectopic expression of an oncogenic BRAF mutant transgene promotes either senescence or differentiation of intestinal stem cells (Carragher et al, 2010; Riemer et al, 2015).…”