APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation

• DOI: 10.1007/s00428-014-1562-1
• Publication Date: 2014-03-04T00:19:03Z
• Authors: Daniela Furlan; Nora Sahnane; Barbara Bernasconi; Milo Frattini; Maria Grazia Tibi...; Francesca Molinari; Alessandro Marando; Lizhi Zhang; Alessandro Vanoli; Selenia Casnedi; Volkan Adsay; Kenji Notohara; Luca Albarello; Sofia Asioli; Fausto Sessa; Carlo Capella; Stefano La Rosa
• Keywords: 0301 basic medicine; Genes, APC; 2734; DNA Mutational Analysis; Gene Dosage; Acinar Cell; Fluorescence; DNA Mutational Analysi; Promoter Regions; 03 medical and health sciences; APC gene; Genetic; Pancrea; Humans; Genes, Tumor Suppressor; Acinar cell carcinoma .; APC gene; Gene loss; Methylation profile; Mutation; Pancreas; Promoter Regions, Genetic; Molecular Biology; Acinar cell carcinoma; In Situ Hybridization; In Situ Hybridization, Fluorescence; Methylation profile; Carcinoma, Acinar Cell; Reverse Transcriptase Polymerase Chain Reaction; Carcinoma; Gene lo; Pancreatic Neoplasm; Cell Biology; DNA Methylation; APC; 3. Good health; Pancreatic Neoplasms; Genes; Mutation; Acinar cell carcinoma; APC gene; Gene loss; Methylation profile; Mutation; Pancreas; Multiplex Polymerase Chain Reaction; Tumor Suppressor; Human

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.