title: Mixed adenoneuroendocrine carcinomas of the gastrointestinal tract: targeted next-generation sequencing suggests a monoclonal origin of the two components.
abstract: BACKGROUND
  Mixed adenoneuroendocrine carcinomas (MANECs) of the gastrointestinal tract are rare neoplasms characterized by coexisting exocrine and neuroendocrine neoplastic components. MANECs' histogenetic classification and molecular characterization remain unclear, significantly affecting the identification of innovative therapeutic options for these tumors.
  
  
  METHODS
  The exocrine and neuroendocrine components of 6 gastrointestinal MANECs were microdissected and subjected to the simultaneous mutation assessment in selected regions of 54 cancer-associated genes using Ion Torrent semiconductor-based next-generation sequencing. Sanger sequencing and immunohistochemistry were used as validation of the mutational status.
  
  
  RESULTS
  A total of 20 driver gene somatic mutations were observed among the 12 neoplastic components investigated. In 11 of 12 (91.7%) samples, at least one mutation was detected; 7 samples (58.3%) were found to have multiple mutations. TP53 gene mutations were the most frequent genetic alterations observed in the series, occurring in 11/12 samples (91.7%). Somatic mutations in other genes were detected at lower frequencies: ATM, CTNNB1, ERBB4, JAK3, KDR, KRAS, RB1.
  
  
  CONCLUSIONS
  Five of the 6 MANECs presented an overlapping mutational profile in both components, suggesting a monoclonal origin of the two MANEC components.
authors.affiliation: ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Scardoni
authors.forename: Emanuele
authors.initials: E
authors.lastname: Vittoria
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.forename: Borislav
authors.initials: B
authors.lastname: Rusev
authors.forename: Samantha
authors.initials: S
authors.lastname: Bersani
authors.forename: Andrea
authors.initials: A
authors.lastname: Mafficini
authors.forename: Marisa
authors.initials: M
authors.lastname: Gottardi
authors.forename: Valeria
authors.initials: V
authors.lastname: Giandomenico
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Malleo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Butturini
authors.forename: Sara
authors.initials: S
authors.lastname: Cingarlini
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53