title: Frequent PTPRK-RSPO3 fusions and RNF43 mutations 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.
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.|Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sekine
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Tanabe
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shinmura
authors.affiliation: Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.|Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hiraoka
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.|Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D007417:Intestinal Polyps / Q000235:genetics / Q000473:pathology; D007422:Intestines / Q000473:pathology; D008297:Male; D009154:Mutation; D050596:Oncogene Fusion; D015513:Oncogene Proteins / Q000235:genetics*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D019699:Thrombospondins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism; D000098907:R-Spondins
chemical_list: D004268:DNA-Binding Proteins; D015513:Oncogene Proteins; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D019699:Thrombospondins; D044767:Ubiquitin-Protein Ligases; D051176:beta Catenin; C475438:RSPO3 protein, human; D000098907:R-Spondins; C496945:RNF43 protein, human; C489852:PTPRK protein, human
keywords: R-spondin; RNF43; WNT; large intestine; traditional serrated adenoma