title: High-throughput mutation profiling identifies novel molecular dysregulation in high-grade intraepithelial neoplasia and early gastric cancers.
abstract: BACKGROUND
  There is still no widely accepted molecular marker available to distinguish between gastric high-grade intraepithelial neoplasia (HG-IEN) and invasive early gastric cancer (EGC).
  
  
  METHODS
  HG-IEN and EGC lesions coexisting in the same patient were manually microdissected from a series of 15 gastrectomies for EGC; 40 ng DNA was used for multiplex PCR amplification using the Ion AmpliSeq Cancer Panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes.
  
  
  RESULTS
  Of the 15 EGCs, 12 presented at least one somatic mutation among the 50 investigated genes, and 6 of these showed multiple driver gene somatic mutations. TP53 mutations were observed in 9 cases; APC mutations were identified in 3 cases; and ATM and STK11 were mutated in 2 cases. Seven HG-IEN lesions shared an identical mutational profile with the EGC from the same patient; 13 mutations observed in APC, ATM, FGFR3, PIK3CA, RB1, STK11, and TP53 genes were shared by both HG-IEN and ECG lesions. CDKN2A, IDH2, MET, and RET mutations were observed only in EGC. TP53 deregulation was further investigated in an independent series of 75 biopsies corresponding to all the phenotypic lesions occurring in the EGC carcinogenetic cascade. p53 nuclear immunoreaction progressively increased along with the dedifferentiation of the lesions (P < 0.001). Overall, 18 of 20 p53-positive lesions showed a TP53 mutated gene.
  
  
  CONCLUSIONS
  Our results support the molecular similarity between HG-IEN and EGC and suggest a relevant role for TP53 in the progression to the invasive phenotype and the use of immunohistochemistry as a surrogate to detect TP53 gene mutations.
authors.affiliation: Department of Pathology and Diagnostics, ARC-NET Research Centre, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.forename: Michele
authors.initials: M
authors.lastname: Simbolo
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.forename: Andrea
authors.initials: A
authors.lastname: Mafficini
authors.forename: Sara
authors.initials: S
authors.lastname: Pilotto
authors.forename: Paola
authors.initials: P
authors.lastname: Capelli
authors.forename: Maria
authors.initials: M
authors.lastname: Bencivenga
authors.forename: Sara
authors.initials: S
authors.lastname: Pecori
authors.forename: Claudio
authors.initials: C
authors.lastname: Luchini
authors.forename: Diogo
authors.initials: D
authors.lastname: Neves
authors.forename: Giona
authors.initials: G
authors.lastname: Turri
authors.forename: Caterina
authors.initials: C
authors.lastname: Vicentini
authors.forename: Licia
authors.initials: L
authors.lastname: Montagna
authors.forename: Anna
authors.initials: A
authors.lastname: Tomezzoli
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.forename: Marco
authors.initials: M
authors.lastname: Chilosi
authors.forename: Giovanni
authors.initials: G
authors.lastname: De Manzoni
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D001706:Biopsy; D002278:Carcinoma in Situ / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D011230:Precancerous Conditions / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53