title: APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation.
abstract: Genetic and epigenetic alterations involved in the pathogenesis of pancreatic acinar cell carcinomas (ACCs) are poorly characterized, including the frequency and role of gene-specific hypermethylation, chromosome aberrations, and copy number alterations (CNAs). A subset of ACCs is known to show alterations in the APC/β-catenin pathway which includes mutations of APC gene. However, it is not known whether, in addition to mutation, loss of APC gene function can occur through alternative genetic and epigenetic mechanisms such as gene loss or promoter methylation. We investigated the global methylation profile of 34 tumor suppressor genes, CNAs of 52 chromosomal regions, and APC gene alterations (mutation, methylation, and loss) together with APC mRNA level in 45 ACCs and related peritumoral pancreatic tissues using methylation-specific multiplex ligation probe amplification (MS-MLPA), fluorescence in situ hybridization (FISH), mutation analysis, and reverse transcription-droplet digital PCR. ACCs did not show an extensive global gene hypermethylation profile. RASSF1 and APC were the only two genes frequently methylated. APC mutations were found in only 7 % of cases, while APC loss and methylation were more frequently observed (48 and 56 % of ACCs, respectively). APC mRNA low levels were found in 58 % of cases and correlated with CNAs. In conclusion, ACCs do not show extensive global gene hypermethylation. APC alterations are frequently involved in the pathogenesis of ACCs mainly through gene loss and promoter hypermethylation, along with reduction of APC mRNA levels.
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Furlan
authors.forename: Nora
authors.initials: N
authors.lastname: Sahnane
authors.forename: Barbara
authors.initials: B
authors.lastname: Bernasconi
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tibiletti
authors.forename: Francesca
authors.initials: F
authors.lastname: Molinari
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marando
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vanoli
authors.forename: Selenia
authors.initials: S
authors.lastname: Casnedi
authors.forename: Volkan
authors.initials: V
authors.lastname: Adsay
authors.forename: Kenji
authors.initials: K
authors.lastname: Notohara
authors.forename: Luca
authors.initials: L
authors.lastname: Albarello
authors.forename: Sofia
authors.initials: S
authors.lastname: Asioli
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
authors.forename: Carlo
authors.initials: C
authors.lastname: Capella
authors.forename: Stefano
authors.initials: S
authors.lastname: La Rosa
mesh_terms: D018267:Carcinoma, Acinar Cell / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018628:Gene Dosage; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D060885:Multiplex Polymerase Chain Reaction; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction