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.
- hepatocellular carcinoma
- cell cycle
- molecular pathology
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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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