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

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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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References

  1. Klimstra DS, Heffess CS, Oertel JE, Rosai J (1992) Acinar cell carcinoma of the pancreas. A clinicopathologic study of 28 cases. Am J Surg Pathol 16:815–837

    Article  CAS  PubMed  Google Scholar 

  2. La Rosa S, Adsay V, Albarello L et al (2012) Clinicopathologic study of 62 acinar cell carcinomas of the pancreas: insights into the morphology and immunophenotype and search for prognostic markers. Am J Surg Pathol 36:1782–1795

    Article  PubMed  Google Scholar 

  3. Moore PS, Beghelli S, Zamboni G, Scarpa A (2003) Genetic abnormalities in pancreatic cancer. Mol Cancer 2:7

    Article  PubMed Central  PubMed  Google Scholar 

  4. McCleary-Wheeler AL, Lomberk GA, Weiss FU et al (2013) Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. Cancer Lett 328:212–221

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. de Wilde RF, Ottenhof NA, Jansen M et al (2011) Analysis of LKB1 mutations and other molecular alterations in pancreatic acinar cell carcinoma. Mod Pathol 24:1229–1236

    Article  PubMed  Google Scholar 

  6. Hoorens A, Lemoine NR, McLellan E et al (1993) Pancreatic acinar cell carcinoma. An analysis of cell lineage markers, p53 expression, and Ki-ras mutation. Am J Pathol 143:685–698

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Pellegata NS, Sessa F, Renault B et al (1994) K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res 54:1556–1560

    CAS  PubMed  Google Scholar 

  8. Moore PS, Orlandini S, Zamboni G et al (2001) Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis. Br J Cancer 84:253–262

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Abraham SC, Wu TT, Hruban RH et al (2002) Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma. Frequent allelic loss on chromosome 11p and alterations in the APC/β-catenin pathway. Am J Pathol 160:953–962

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Hosoda W, Sasaki E, Muraka IY, Yamao K, Shimizu Y, Yatabe Y (2013) BCL10 as a useful marker for pancreatic acinar cell carcinoma, especially using endoscopic ultrasound cytology specimens. Pathol Int 63:176–182

    Article  CAS  PubMed  Google Scholar 

  11. Taruscio D, Paradisi S, Zamboni G, Rigaud G, Falconi M, Scarpa A (2000) Pancreatic acinar carcinoma shows a distinct pattern of chromosomal imbalances by comparative genomic hybridization. Genes Chromosome Cancer 28:294–299

    Article  CAS  Google Scholar 

  12. Dewald GW, Smyrk TC, Thorland EC et al (2009) Fluorescence in situ hybridization to visualize genetic abnormalities in interphase cells of acinar cell carcinoma, ductal adenocarcinoma, and islet cell carcinoma of the pancreas. Mayo Clin Proc 84:801–810

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. van Dongen JJ, Langerak AW, Bruggemann M et al (2003) Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 17:2257–2317

    Article  PubMed  Google Scholar 

  14. La Rosa S, Marando A, Furlan D, Sahnane N, Capella C (2012) Colorectal poorly differentiated neuroendocrine carcinomas and mixed adenoneuroendocrine carcinomas: insights into the diagnostic immunophenotype, assessment of methylation profile, and search for prognostic markers. Am J Surg Pathol 36:601–611

    Article  PubMed  Google Scholar 

  15. Furlan D, Sahnane N, Mazzoni M et al (2013) Diagnostic utility of MS-MLPA in DNA methylation profiling of adenocarcinomas and neuroendocrine carcinomas of the colon-rectum. Virchows Arch 462:47–56

    Article  CAS  PubMed  Google Scholar 

  16. Homing-Holzel C, Savola S (2012) Multiplex ligation-dependent probe amplification (MLPA) in tumor diagnostics and prognostics. Diagn Mol Pathol 21:189–206

    Article  Google Scholar 

  17. Tibiletti MG, Martin V, Bernasconi B et al (2009) BCL2, BCL6, MYC, MALT 1, and BCL10 rearrangements in nodal diffuse large B-cell lymphomas: a multicenter evaluation of a new set of fluorescence in situ hybridization probes and correlation with clinical outcome. Hum Pathol 40:645–652

    Article  CAS  PubMed  Google Scholar 

  18. Frattini M, Balestra D, Suardi S et al (2004) Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res 10:4015–4021

    Article  CAS  PubMed  Google Scholar 

  19. Sato N, Goggins M (2006) Epigenetic alterations in intraductal papillary mucinous neoplasms of the pancreas. J Hepatobiliary Pancreat Surg 13:280–285

    Article  PubMed  Google Scholar 

  20. Dammann R, Schagdarsurengin U, Liu L et al (2003) Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma. Oncogene 22:3806–3812

    Article  CAS  PubMed  Google Scholar 

  21. Gerdes B, Wild A, Wittenberg J et al (2003) Tumor-suppressing pathways in cystic pancreatic tumors. Pancreas 26:42–48

    Article  CAS  PubMed  Google Scholar 

  22. Omura N, Li CP, Li A et al (2008) Genome-wide profiling of methylated promoters in pancreatic adenocarcinoma. Cancer Biol Ther 7:1146–1156

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Vincent A, Omura N, Hong SM, Jaffe A, Eshleman J, Goggins M (2011) Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. Clin Cancer Res 17:4341–4354

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Fukushima N, Walter KM, Uek T et al (2003) Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juice. Cancer Biol Ther 2:78–83

    PubMed  Google Scholar 

  25. Park JK, Ryu JK, Yoon WJ et al (2012) The role of quantitative NPTX2 hypermethylation as a novel serum diagnostic marker in pancreatic cancer. Pancreas 41:95–101

    Article  CAS  PubMed  Google Scholar 

  26. Pfeifer GP, Dammann R (2005) Methylation of the tumor suppressor gene RASSF1A in human tumors. Biochemistry 70:576–583

    CAS  PubMed  Google Scholar 

  27. Ueki T, Toyota M, Sohn T et al (2000) Hypermethylation of multiple genes in pancreatic adenocarcinomas. Cancer Res 60:1835–1839

    CAS  PubMed  Google Scholar 

  28. Stefanoli M, Furlan D, Sahnane N, La Rosa S, Romualdi C, Sessa F, Capella C (2013) DNA methylation profile identifies prognostic clusters of pancreatic neuroendocrine tumors [abstract]. Mod Pathol 26(Suppl 2):137A

    Google Scholar 

  29. Malpeli G, Amato E, Dandrea M et al (2011) Methylation-associated down-regulation of RASSF1A and up-regulation of RASSF1C in pancreatic endocrine tumors. BMC Cancer 11:351

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. van Engeland M, Roemen GM, Brink M et al (2002) K-ras mutations and RASSF1A promoter methylation in colorectal cancer. Oncogene 21:3792–3795

    Article  PubMed  Google Scholar 

  31. Kang S, Kim HS, Seo SS, Park SY, Sidransky D, Dong SM (2007) Inverse correlation between RASSF1A hypermethylation, KRAS and BRAF mutations in cervical adenocarcinoma. Gynecol Oncol 105:662–666

    Article  CAS  PubMed  Google Scholar 

  32. Agathanggelou A, Cooper WN, Latif F (2005) Role of the Ras-association domain family 1 tumor suppressor gene in human cancers. Cancer Res 65:3497–3508

    Article  CAS  PubMed  Google Scholar 

  33. Saelee P, Wongkham S, Chariyalertsak S, Petmitr S, Chuensumran U (2010) RASSF1A promoter hypermethylation as a prognostic marker for hepatocellular carcinoma. Asian Pac J Cancer Prev 11:1677–1681

    PubMed  Google Scholar 

  34. Gomperts BN, Walser TC, Spira A, Dubinett SM (2013) Enriching the molecular definition of the airway “field of cancerization”: establishing new paradigms for the patient at risk for lung cancer. Cancer Prev Res 6:4–7

    Article  CAS  Google Scholar 

  35. Knudson AG Jr (1978) Retinoblastoma: a prototypic hereditary neoplasm. Semin Oncol 5:57–60

    PubMed  Google Scholar 

  36. Klimstra DS (2007) Nonductal neoplasms of the pancreas. Mod Pathol 20:S94–S112

    Article  PubMed  Google Scholar 

  37. Dikovskaya D, Schiffmann D, Newton IP et al (2007) Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis. J Cell Biol 176:183–195

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Rusan NM, Peifer M (2008) Original CIN: reviewing roles for APC in chromosome instability. J Cell Biol 181:719–726

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy

    Daniela Furlan, Nora Sahnane, Barbara Bernasconi, Alessandro Marando, Fausto Sessa & Carlo Capella

  2. Laboratory of Molecular Diagnostic, Institute of Pathology, Locarno, Switzerland

    Milo Frattini & Francesca Molinari

  3. Department of Pathology, Ospedale di Circolo, Viale Borri 57, 21100, Varese, Italy

    Maria Grazia Tibiletti, Fausto Sessa & Stefano La Rosa

  4. Department of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA

    Lizhi Zhang

  5. Department of Pathology, University of Pavia, Pavia, Italy

    Alessandro Vanoli

  6. Department of Pathology, Hospital de Hautepierre, Strasbourg, France

    Selenia Casnedi

  7. Department of Pathology, Emory University, Atlanta, GA, USA

    Volkan Adsay

  8. Department of Pathology, Kurashiki Central Hospital, Kurashiki, Japan

    Kenji Notohara

  9. Pathology Unit, San Raffaele Scientific Institute, Milan, Italy

    Luca Albarello

  10. Department of Medical Sciences, University of Turin, Turin, Italy

    Sofia Asioli

Authors
  1. Daniela Furlan
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  2. Nora Sahnane
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  3. Barbara Bernasconi
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  4. Milo Frattini
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  6. Francesca Molinari
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  7. Alessandro Marando
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  8. Lizhi Zhang
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  9. Alessandro Vanoli
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  10. Selenia Casnedi
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  11. Volkan Adsay
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  12. Kenji Notohara
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  13. Luca Albarello
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  14. Sofia Asioli
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  15. Fausto Sessa
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  16. Carlo Capella
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  17. Stefano La Rosa
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Corresponding author

Correspondence to Stefano La Rosa.

Additional information

Daniela Furlan and Nora Sahnane contributed equally to this work.

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Furlan, D., Sahnane, N., Bernasconi, B. et al. APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation. Virchows Arch 464, 553–564 (2014). https://doi.org/10.1007/s00428-014-1562-1

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  • DOI: https://doi.org/10.1007/s00428-014-1562-1

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