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

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)553-564
Number of pages12
JournalVirchows Archiv
Volume464
Issue number5
DOIs
Publication statusPublished - 2014

Fingerprint

Acinar Cell Carcinoma
Pancreas
Methylation
APC Genes
Genes
Mutation
Epigenomics
Messenger RNA
Catenins
Gene Dosage
Tumor Suppressor Genes
Fluorescence In Situ Hybridization
Gene Frequency
Chromosome Aberrations
Reverse Transcription
Ligation
Polymerase Chain Reaction

Keywords

  • Acinar cell carcinoma
  • APC gene
  • Gene loss
  • Methylation profile
  • Mutation
  • Pancreas

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Cite this

APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation. / Furlan, Daniela; Sahnane, Nora; Bernasconi, Barbara; Frattini, Milo; Tibiletti, Maria Grazia; Molinari, Francesca; Marando, Alessandro; Zhang, Lizhi; Vanoli, Alessandro; Casnedi, Selenia; Adsay, Volkan; Notohara, Kenji; Albarello, Luca; Asioli, Sofia; Sessa, Fausto; Capella, Carlo; La Rosa, Stefano.

In: Virchows Archiv, Vol. 464, No. 5, 2014, p. 553-564.

Research output: Contribution to journalArticle

Furlan, D, Sahnane, N, Bernasconi, B, Frattini, M, Tibiletti, MG, Molinari, F, Marando, A, Zhang, L, Vanoli, A, Casnedi, S, Adsay, V, Notohara, K, Albarello, L, Asioli, S, Sessa, F, Capella, C & La Rosa, S 2014, 'APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation', Virchows Archiv, vol. 464, no. 5, pp. 553-564. https://doi.org/10.1007/s00428-014-1562-1
Furlan, Daniela ; Sahnane, Nora ; Bernasconi, Barbara ; Frattini, Milo ; Tibiletti, Maria Grazia ; Molinari, Francesca ; Marando, Alessandro ; Zhang, Lizhi ; Vanoli, Alessandro ; Casnedi, Selenia ; Adsay, Volkan ; Notohara, Kenji ; Albarello, Luca ; Asioli, Sofia ; Sessa, Fausto ; Capella, Carlo ; La Rosa, Stefano. / APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation. In: Virchows Archiv. 2014 ; Vol. 464, No. 5. pp. 553-564.
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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.",
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T1 - APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation

AU - Furlan, Daniela

AU - Sahnane, Nora

AU - Bernasconi, Barbara

AU - Frattini, Milo

AU - Tibiletti, Maria Grazia

AU - Molinari, Francesca

AU - Marando, Alessandro

AU - Zhang, Lizhi

AU - Vanoli, Alessandro

AU - Casnedi, Selenia

AU - Adsay, Volkan

AU - Notohara, Kenji

AU - Albarello, Luca

AU - Asioli, Sofia

AU - Sessa, Fausto

AU - Capella, Carlo

AU - La Rosa, Stefano

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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KW - APC gene

KW - Gene loss

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KW - Mutation

KW - Pancreas

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