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Original article
Polyploidy spectrum: a new marker in HCC classification
  1. Myriam Bou-Nader1,
  2. Stefano Caruso2,
  3. Romain Donne1,
  4. Séverine Celton-Morizur1,
  5. Julien Calderaro3,4,
  6. Géraldine Gentric5,6,
  7. Mathilde Cadoux1,
  8. Antoine L’Hermitte7,
  9. Christophe Klein8,
  10. Thomas Guilbert9,
  11. Miguel Albuquerque10,
  12. Gabrielle Couchy2,
  13. Valérie Paradis11,
  14. Jean-Pierre Couty1,
  15. Jessica Zucman-Rossi2,
  16. Chantal Desdouets1
  1. 1Team Proliferation Stress and Liver Physiopathology, Genome and Cancer, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
  2. 2Team Functional Genomics of Solid Tumors, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Équipe Labellisée Ligue Contre le Cancer, Paris, France
  3. 3INSERM U1162, Paris, France
  4. 4Department of Pathology, Hopital Henri Mondor, Creteil, France
  5. 5Stress and Cancer Laboratory, Équipe Labelisée LNCC, Institut Curie, Paris, France
  6. 6INSERM U830, Paris, France
  7. 7Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
  8. 8INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Paris, France
  9. 9Institut Cochin, Paris, France
  10. 10Department of Pathology, Beaujon Hospital, Clichy, France
  11. 11Hopital Beaujon, Clichy, France
  1. Correspondence to Dr Chantal Desdouets, Team Proliferation Stress and Liver Physiopathology, Genome and Cancer, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris 75006, France; chantal.desdouets{at}inserm.fr

Abstract

Objectives Polyploidy is a fascinating characteristic of liver parenchyma. Hepatocyte polyploidy depends on the DNA content of each nucleus (nuclear ploidy) and the number of nuclei per cell (cellular ploidy). Which role can be assigned to polyploidy during human hepatocellular carcinoma (HCC) development is still an open question. Here, we investigated whether a specific ploidy spectrum is associated with clinical and molecular features of HCC.

Design Ploidy spectra were determined on surgically resected tissues from patients with HCC as well as healthy control tissues. To define ploidy profiles, a quantitative and qualitative in situ imaging approach was used on paraffin tissue liver sections.

Results We first demonstrated that polyploid hepatocytes are the major components of human liver parenchyma, polyploidy being mainly cellular (binuclear hepatocytes). Across liver lobules, polyploid hepatocytes do not exhibit a specific zonation pattern. During liver tumorigenesis, cellular ploidy is drastically reduced; binuclear polyploid hepatocytes are barely present in HCC tumours. Remarkably, nuclear ploidy is specifically amplified in HCC tumours. In fact, nuclear ploidy is amplified in HCCs harbouring a low degree of differentiation and TP53 mutations. Finally, our results demonstrated that highly polyploid tumours are associated with a poor prognosis.

Conclusions Our results underline the importance of quantification of cellular and nuclear ploidy spectra during HCC tumorigenesis.

  • liver
  • hepatocellular carcinoma
  • histopathology
  • cell cycle
  • molecular pathology

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Footnotes

  • RD and SC-M contributed equally.

  • MB-N and SC contributed equally.

  • Contributors MBN designed, performed and analysed the experiments, compiled the figures and wrote the manuscript. SC analysed the experiments, compiled the data with statistical analysis /designed the figures and wrote the manuscript. JC designed and analysed the experiments, and compiled the data. RD, GG, CM, LA, TG, CK, MA and GC performed experimental research. VP and JPC analysed the data and provided critical help on the manuscript. SCM analysed the data, designed the figures and provided critical help on the manuscript. JZR analysed the experiments, funded the project and provided critical help on the manuscript. CD designed and performed the experiments, analysed the data, funded the project and wrote the manuscript.

  • Funding This study was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), the Institut National du Cancer (PRTK-2017, PLBIO 2018-140), Fondation ARC (Association de Recherche sur le Cancer), Ligue Contre le Cancer (Comité de Paris), the Cancéropôle Ile-de-France (Emergence 2015), The Association Française pour l’Etude du Foie (AFEF-SUBV 2017), EVA-Plan Cancer INSERM HTE and the Agence Nationale de Recherche ANR (ANR-16-CE14).

  • Competing interests None declared.

  • Ethics approval The study was approved by the Institutional Review Board committees (CCPRB Paris Saint Louis, 1997, 2004 and 2010)

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Obtained.

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