title: Genes involved in angiogenesis and mTOR pathways are frequently mutated in Asian patients with pancreatic neuroendocrine tumors.
abstract: Introduction:To address the issue of limited data on and inconsistent findings for genetic alterations in pancreatic neuroendocrine tumors (pNETs), we analyzed sequences of known pNET-associated genes for their impact on clinical outcomes in a Taiwanese cohort.Methods:Tissue samples from 40 patients with sporadic pNETs were sequenced using a customized sequencing panel that analyzed 43 genes with either an established or potential association with pNETs. Genetic mutations and clinical outcomes were analyzed for potential associations.Results:Thirty-three patients (82.5%) survived for a median 5.9 years (range, 0.3-18.4) of follow up. The median number of mutations per patient was 3 (range, 0-16). The most frequent mutations were inATRX(28%),MEN1(28%),ASCL1(28%),TP53(20%),mTOR(20%),ARID1A(20%), andVHL(20%). The mutation frequencies in the MEN1 (includingMEN1/PSIP1/ARID1A), mTOR (including mTOR/PIK3CA/AKT1/PTEN/TS1/TSC2/ATM), DAXX/ATRX, and angiogenesis (includingVHL/ANGPT1/ANGPT2/HIF1A) pathways were 48%, 48%, 38%, and 45%, respectively. Mutations inATRXwere associated with WHO grade I pNET (vs. grade II or III, p = 0.043), and so were those in genes involved in angiogenesis (p = 0.002). Patients with mutated MEN1 and DAXX/ATRX pathways showed a trend toward better survival, compared to patients with the wild-type genes (p = 0.08 and 0.12, respectively).Conclusion:Genetic profiles of Asian patients with pNETs were distinct from Caucasian patient profiles. Asian patients with pNETs were more frequently mutated for the mTOR and angiogenesis pathways. This could partially explain the better outcome observed for targeted therapy in Asian patients with pNETs.
authors.affiliation: Department of Hematology-Oncology, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taiwan.
authors.forename: Po-Han
authors.initials: PH
authors.lastname: Lin
authors.affiliation: Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Yeh
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan;; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Shyr
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan;; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Fang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan;; Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shin-E
authors.initials: SE
authors.lastname: Wang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan;; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan;; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Peter Mu-Hsin
authors.initials: PM
authors.lastname: Chang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ming-Han
authors.initials: MH
authors.lastname: Chen
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan;; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Hung
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan;; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Li
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan;; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yee
authors.initials: Y
authors.lastname: Chao
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan;; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D044466:Asian People; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics*; D018358:Neuroendocrine Tumors / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000075924:X-linked Nuclear Protein; C112476:ARID1A protein, human; C065500:ASCL1 protein, human; C495901:TP53 protein, human; C546842:MTOR protein, human; C092332:ATRX protein, human; C497446:VHL protein, human
keywords: angiogenesis; genetic mutation; mTOR pathway; neuroendocrine tumor