In Situ Hepatitis C NS3 Protein Detection Is Associated with High Grade Features in Hepatitis C-Associated B-Cell Non-Hodgkin Lymphomas

Danielle Canioni; Jean-Marie Michot; Pascaline Rabiega; Thierry J Molina; Frédéric Charlotte; Thierry Lazure; Frédéric Davi; Catherine Settegrana; Françoise Berger; Laurent Alric; Patrice Cacoub; Benjamin Terrier; Felipe Suarez; David Sibon; Jehan Dupuis; Cyrille Feray; Hervé Tilly; Stanislas Pol; Bénédicte Deau Fischer; Sandrine Roulland; Catherine Thieblemont; Véronique Leblond; Fabrice Carrat; Olivier Hermine; Caroline Besson; national ANRS HC13 LymphoC study

doi:10.1371/journal.pone.0156384

In Situ Hepatitis C NS3 Protein Detection Is Associated with High Grade Features in Hepatitis C-Associated B-Cell Non-Hodgkin Lymphomas

PLoS One. 2016 Jun 3;11(6):e0156384. doi: 10.1371/journal.pone.0156384. eCollection 2016.

Authors

Danielle Canioni¹, Jean-Marie Michot², Pascaline Rabiega³, Thierry J Molina¹, Frédéric Charlotte⁴, Thierry Lazure⁵, Frédéric Davi⁶, Catherine Settegrana⁶, Françoise Berger⁷, Laurent Alric⁸, Patrice Cacoub⁹, Benjamin Terrier⁹, Felipe Suarez^{10

11}, David Sibon^{10

11}, Jehan Dupuis¹², Cyrille Feray¹³, Hervé Tilly¹⁴, Stanislas Pol¹⁵, Bénédicte Deau Fischer¹⁶, Sandrine Roulland¹⁷, Catherine Thieblemont¹⁸, Véronique Leblond¹⁹, Fabrice Carrat³, Olivier Hermine^{10

11}, Caroline Besson²⁰; national ANRS HC13 LymphoC study

Affiliations

¹ Department of Pathology, Paris Descartes University, AP-HP, Sorbonne Paris Cité, Hôpital Necker, Paris, France.
² Department of Hematology and Drug Development, Gustave Roussy Institute, Villejuif, F-94805, France.
³ Institut Pierre Louis d'Epidémiologie et de Santé Publique INSERM UMR S1136, Paris 6 Pierre et Marie Curie University, Paris, France.
⁴ Department of Pathology, HôpitalPitié-Salpétrière, Paris 6 Pierre et Marie Curie University, Paris, France.
⁵ Department of Pathology, Paris 11 Sud University, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
⁶ Department of Biological Hematology, Paris 6 Pierre et Marie Curie University, AP-HP, Hôpital Pitié-Salpétrière, Paris, France.
⁷ Department of Pathology, Hopital Lyon Sud, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France.
⁸ Department of Internal Medicine and Digestive Diseases, Toulouse 3 University, UMR 152 IRD, Hôpital Purpan, Toulouse, France.
⁹ Department of Internal Medicine, APHP, Hôpital Pitié-Salpétrière, Paris 6 Pierre et Marie Curie University, UMR 7211, INSERM, UMR S 959, CNRS, Paris, France.
¹⁰ Department of Adult Hematology, Paris 5 Descartes University, AP-HP, Hôpital Necker, Paris, France.
¹¹ Imagine Institute, University Sorbonne Paris Cité, INSERM U 1163, CNRS ERL 8254, Paris, France.
¹² Department of Lymphoid Malignancies and Clinical Hematology, Paris 12 Est Créteil University, AP-HP, Hôpital Henri-Mondor, Créteil, France.
¹³ Department of Hepatology, Nantes University, Hôpital de Nantes, Nantes, France.
¹⁴ Department of Hematology, Rouen University, Centre Henri Becquerel, Rouen, France.
¹⁵ Department of Hepatology, Paris 5 Descartes University, INSERM U-1016, AP-HP, Hôpital Cochin, Paris, France.
¹⁶ Department of Hematology, Paris Descartes University, AP-HP, Hôpital Cochin, Paris, France.
¹⁷ Centre d'Immunologie de Marseille Luminy, Aix-Marseille Université INSERM U1104 CNRS UMR7280, Marseille, France.
¹⁸ Department of Hemato-oncology, University Paris Sorbonne P7, INSERM U728, AP-HP, Hôpital Saint-Louis, Paris, France.
¹⁹ Department of Clinical Hematology, Paris 6 Pierre et Marie Curie, Paris, France.
²⁰ Department of Internal Medicine & Clinical Immunology Biological Immunology and Hematology, Paris 11 Sud University, AP-HP, Hôpital Bicêtre, INSERM U 1184, Le Kremlin-Bicêtre, France.

Abstract

Hepatitis C Virus (HCV) infection is associated with the B-cell non-Hodgkin lymphomas (NHL), preferentially marginal zone lymphomas (MZL) and diffuse large B-cell lymphomas (DLBCL). While chronic antigenic stimulation is a main determinant of lymphomagenesis in marginal zone lymphomas (MZL), a putative role of HCV infection of B-cells is supported by in vitro studies. We performed a pathological study within the "ANRS HC-13 LymphoC" observational study focusing on in situ expression of the oncogenic HCV non structural 3 (NS3) protein. Lympho-C study enrolled 116 HCV-positive patients with B-NHL of which 86 histological samples were collected for centralized review. Main histological subtypes were DLBCL (36%) and MZL (34%). Almost half of DLBCL (12/26) were transformed from underlying small B-cell lymphomas. NS3 immunostaining was found positive in 17 of 37 tested samples (46%). There was a striking association between NS3 detection and presence of high grade lymphoma features: 12 out of 14 DLBCL were NS3+ compared to only 4 out of 14 MZL (p = 0.006). Moreover, 2 among the 4 NS3+ MZL were enriched in large cells. Remarkably, this study supports a new mechanism of transformation with a direct oncogenic role of HCV proteins in the occurrence of high-grade B lymphomas.

MeSH terms

Adult
Aged
Aged, 80 and over
B-Lymphocytes / metabolism
B-Lymphocytes / virology
Female
Hepacivirus / metabolism*
Hepatitis C / complications*
Hepatitis C / virology*
Humans
Lymphoma, B-Cell / etiology*
Lymphoma, B-Cell / virology*
Male
Middle Aged
Viral Nonstructural Proteins / genetics
Viral Nonstructural Proteins / metabolism*

Substances

Viral Nonstructural Proteins

Grants and funding

This research has been funded by Inserm-ANRS (Institut national de la santé et de la recherche médicale – France Recherche Nord&Sud SIDA-HIV Hépatites) 101, rue de Tolbiac, 75013 Paris, France. Grant LymphoC-HC13. http://www.anrs.fr/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.