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Histo-molecular characterization of pancreatic cancer with microsatellite instability: intra-tumor heterogeneity, B2M inactivation, and the importance of metastatic sites.

Authors
  • Luchini, Claudio1
  • Mafficini, Andrea2, 3
  • Chatterjee, Deyali4
  • Piredda, Maria L3
  • Sciammarella, Concetta3
  • Navale, Pooja5
  • Malleo, Giuseppe6
  • Mattiolo, Paola2
  • Marchegiani, Giovanni7, 8
  • Pea, Antonio9
  • Salvia, Roberto6
  • Brosens, Lodewijk A7, 8
  • Paolino, Gaetano2
  • Mastrosimini, Maria G2
  • Silvestris, Nicola9
  • Milella, Michele10
  • Cheng, Liang11
  • Adsay, Volkan N12
  • Lawlor, Rita T3
  • Scarpa, Aldo13, 14
  • 1 Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Piazzale Scuro, 10, 37134, Verona, Italy. [email protected] , (Italy)
  • 2 Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Piazzale Scuro, 10, 37134, Verona, Italy. , (Italy)
  • 3 ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy. , (Italy)
  • 4 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Pathology and Immunology, Washington University, St. Louis, MO, USA.
  • 6 Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. , (Italy)
  • 7 Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. , (Netherlands)
  • 8 Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. , (Netherlands)
  • 9 IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, and Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy. , (Italy)
  • 10 Department of Medicine, Section of Oncology, University and Hospital Trust of Verona, Verona, Italy. , (Italy)
  • 11 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. , (India)
  • 12 Department of Pathology, Koç University Hospitals, Istanbul, Turkey. , (Turkey)
  • 13 Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Piazzale Scuro, 10, 37134, Verona, Italy. [email protected] , (Italy)
  • 14 ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy. [email protected] , (Italy)
Type
Published Article
Journal
Virchows Archiv
Publisher
Springer Berlin Heidelberg
Publication Date
Jun 01, 2022
Volume
480
Issue
6
Pages
1261–1268
Identifiers
DOI: 10.1007/s00428-021-03205-3
PMID: 34613461
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Pancreatic ductal adenocarcinoma (PDAC) with microsatellite instability (MSI)/defective mismatch repair (dMMR) is the only subtype of pancreatic cancer with potential response to immunotherapy. Here, we report the histo-molecular characterization of MSI/dMMR PDAC with immunohistochemistry, MSI-based PCR, and next-generation sequencing. Five paradigmatic cases have been identified. The main results include the first report in pancreatic cancer of MSI/dMMR intra-tumor heterogeneity, the presence of microsatellite-stable metastases from MSI/dMMR primary and recurrent B2M gene inactivation, which may confer resistance to immunotherapy. In addition to the classic PDAC drivers, ARID1A was the most common mutated gene in the cohort. Intra-tumor heterogeneity, B2M inactivation, and metastatic sites should be carefully considered in MSI/dMMR PDAC, which should also be investigated in routine diagnostic practice with specific molecular analysis. The chromatin remodeler ARID1A represents another potential driver gene in this context. © 2021. Springer-Verlag GmbH Germany, part of Springer Nature.

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