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Small-bowel carcinomas associated with celiac disease: transcriptomic profiling shows predominance of microsatellite instability-immune and mesenchymal subtypes

  • Francesca Rizzo
  • Alessandro Vanoli
  • Nora Sahnane
  • Roberta Cerutti
  • Davide Trapani
  • Antonio Rinaldi
  • Assunta Sellitto
  • Carolina Ciacci
  • Umberto Volta
  • Vincenzo Villanacci
  • Antonio Calabrò
  • Giovanni Arpa
  • Ombretta Luinetti
  • Marco Paulli
  • Enrico Solcia
  • Antonio Di Sabatino
  • Fausto Sessa
  • Alessandro Weisz
  • Daniela FurlanEmail author
Original Article
Part of the following topical collections:
  1. Quality in Pathology

Abstract

Celiac disease (CD) is a risk factor for developing small-bowel carcinoma with a 14-fold higher risk compared with general population. As small-bowel carcinomas associated with CD (CD-SBCs) are extremely rare, very few molecular data are available about their pathogenesis, and information about their transcriptomic profiling is lacking. We generated RNA-seq data on 13 CD-SBCs, taken from the largest well-characterized series published so far, collected by the Small Bowel Cancer Italian Consortium, and compared the tumor transcriptional signatures with the four Consensus Molecular Subtypes (CMS) of colorectal carcinoma by applying the “CMS classifier.” CpG Island Methylator Phenotype (CIMP) was evaluated using methylation-sensitive multiple ligation-dependent probe amplification. Up to 12 of 13 cancers fell within the two main subtypes exhibiting high immune and inflammatory signatures, i.e., subtypes 1 and 4. The first and predominant subset was commonly microsatellite unstable, and exhibited CIMP and high CD3+ and CD8+ T cell infiltration. Moreover, it showed increased expression of genes associated with T helper 1 and natural killer cell infiltration, as well as upregulation of apoptosis, cell cycle progression, and proteasome pathways. By contrast, cancers falling in subtype 4 showed prominent transforming growth factor-β activation and were characterized by complement-associated inflammation, matrix remodeling, cancer-associated stroma production, and angiogenesis. Parallel histologic and histochemical analysis confirmed such tumor subtyping. In conclusion, two molecular subtypes have been consistently identified in our series of CD-SBCs, a microsatellite instability-immune and a mesenchymal subtype, the former likely associated with an indolent and the latter with a worse tumor behavior.

Keywords

Transcriptomic profiling RNA-sequencing Small-bowel carcinoma Celiac disease 

Notes

Acknowledgments

We thank all the Collaborators of the “Small Bowel Cancer Italian Consortium.”

Funding information

This study was supported by the University of Insubria (to Prof. Furlan, FAR project 2016-2017), the Italian Association for Cancer Research (AIRC Grant: IG-17426), and Regione Campania (“La Campania lotta contro il cancro” project Rare-Plat-Net, CUP: B63D18000380007; and project GENOMAeSALUTE, CUP: B41C17000080007) and Genomix4Life to Prof. Weisz. This research was also supported by a grant of the Italian Ministry of Education, University and Research (MIUR), to the Department of Molecular Medicine of the University of Pavia under the initiative “Dipartimenti di Eccellenza” (2018–2022) to Prof. Marco Paulli and by Fondazione IRCCS Policlinico San Matteo to Dr. Ombretta Luinetti. A.S. is a PhD student of the Research Doctorate in “Sciences and Biomedical Technologies–XXXI Cycle,” University Roma 3.

Compliance with ethical standards

Declaration of Helsinki and its revision and was approved by the Ethics Committee of the IRCCS San Matteo Hospital Foundation, Italy (no. 20140018113, on 22nd September 2014).

Conflict of interest

The authors have no conflicts of interest

Ethical responsibilities of authors section

Study design: DF, FR, AV, ES; acquisition, analysis, or interpretation of data: all authors

Drafting the work or revising it critically: all authors

Final approval of the version to be published: all authors

Agreement to be accountable for all aspects of the work: all authors

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Francesca Rizzo
    • 1
    • 2
  • Alessandro Vanoli
    • 3
  • Nora Sahnane
    • 4
  • Roberta Cerutti
    • 4
  • Davide Trapani
    • 4
  • Antonio Rinaldi
    • 1
  • Assunta Sellitto
    • 1
  • Carolina Ciacci
    • 5
  • Umberto Volta
    • 6
  • Vincenzo Villanacci
    • 7
  • Antonio Calabrò
    • 8
  • Giovanni Arpa
    • 3
  • Ombretta Luinetti
    • 3
  • Marco Paulli
    • 3
  • Enrico Solcia
    • 3
  • Antonio Di Sabatino
    • 9
  • Fausto Sessa
    • 4
  • Alessandro Weisz
    • 1
    • 2
  • Daniela Furlan
    • 4
    Email author
  1. 1.Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and DentistrySalernoItaly
  2. 2.Medical Genomics Program, Department of Onco-Haematology SS. Giovanni di Dio e Ruggi d’Aragona University HospitalUniversity of SalernoSalernoItaly
  3. 3.Department of Molecular MedicineUniversity of Pavia and IRCCS San Matteo Hospital FoundationPaviaItaly
  4. 4.Unit of Pathology, Dept. of Medicine and Surgery and Research Center for the Study of Hereditary and Familial TumorsUniversity of InsubriaVareseItaly
  5. 5.Gastrointestinal Unit, Department of Medicine, Surgery and Dentistry, Scuola Medica SalernitanaUniversity of SalernoSalernoItaly
  6. 6.Department of Medical and Surgical Sciences, St. Orsola-Malpighi HospitalUniversity of BolognaBolognaItaly
  7. 7.Institute of PathologyBresciaItaly
  8. 8.Department of Experimental and Clinical Biomedical Sciences, Gastroenterology UnitUniversity of FlorenceFlorenceItaly
  9. 9.Department of Internal MedicineUniversity of Pavia and IRCCS San Matteo Hospital FoundationPaviaItaly

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