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Virchows Archiv

, Volume 464, Issue 5, pp 553–564 | Cite as

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

  • Daniela Furlan
  • Nora Sahnane
  • Barbara Bernasconi
  • Milo Frattini
  • Maria Grazia Tibiletti
  • 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
Original Article

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.

Keywords

Acinar cell carcinoma APC gene Gene loss Methylation profile Mutation Pancreas 

Notes

Acknowledgments

The authors thank Prof. Luigi Terracciano for providing some normal pancreatic tissues and Dr. Marco Bianchi for his helpful technical advice.

The authors also thank Everett Rhonda for the revision of English writing.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Daniela Furlan
    • 1
  • Nora Sahnane
    • 1
  • Barbara Bernasconi
    • 1
  • Milo Frattini
    • 2
  • Maria Grazia Tibiletti
    • 3
  • Francesca Molinari
    • 2
  • Alessandro Marando
    • 1
  • Lizhi Zhang
    • 4
  • Alessandro Vanoli
    • 5
  • Selenia Casnedi
    • 6
  • Volkan Adsay
    • 7
  • Kenji Notohara
    • 8
  • Luca Albarello
    • 9
  • Sofia Asioli
    • 10
  • Fausto Sessa
    • 1
    • 3
  • Carlo Capella
    • 1
  • Stefano La Rosa
    • 3
  1. 1.Department of Surgical and Morphological SciencesUniversity of InsubriaVareseItaly
  2. 2.Laboratory of Molecular DiagnosticInstitute of PathologyLocarnoSwitzerland
  3. 3.Department of PathologyOspedale di CircoloVareseItaly
  4. 4.Department of Anatomic PathologyMayo ClinicRochesterUSA
  5. 5.Department of PathologyUniversity of PaviaPaviaItaly
  6. 6.Department of PathologyHospital de HautepierreStrasbourgFrance
  7. 7.Department of PathologyEmory UniversityAtlantaUSA
  8. 8.Department of PathologyKurashiki Central HospitalKurashikiJapan
  9. 9.Pathology Unit, San Raffaele Scientific InstituteMilanItaly
  10. 10.Department of Medical SciencesUniversity of TurinTurinItaly

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