EZH2 alterations in follicular lymphoma: biological and clinical correlations

Blood Cancer Journal - Tập 7 Số 4 - Trang e555-e555
Sarah Huet1,2, Luc Xerri3, Bruno Tesson4, Sylvain Mareschal5, Sébastien Taix3, Lénaïg Mescam-Mancini3, Emilie Sohier5, Marjorie Carrère2, Julien Lazarovici6,7, Olivier Casasnovas8, Laurie Tonon5, Sandrine Boyault9, Sandrine Hayette1,2, Corinne Haïoun10,11, Bettina Fabiani12, Alain Viari13,14, Fabrice Jardin5, Gilles Salles1,2
1Service d'hématologie [Hôpital Edouard Herriot - HCL] (5, place d'Arsonval - 69437 LYON cedex 03 - France)
2UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon (28, rue Laennec - 69373 Lyon - France)
3IPC - Institut Paoli-Calmettes (232 Boulevard de Sainte-Marguerite 13009 Marseille - France)
4CALYM - Institut Carnot Lymphome (Consortium, Centre Hospitalier Lyon-Sud, Secteur Sainte Eugénie, pavillon 6E 69495 Pierre-Benite Cedex - France)
5Synergie Lyon Cancer-Platform of Bioinformatics-Gilles Thomas (28, rue Laënnec 69008 Lyon - France)
6Département d'hématologie [Gustave Roussy] (Villejuif - France)
7Université Paris-Saclay (Bâtiment Bréguet, 3 Rue Joliot Curie 2e ét, 91190 Gif-sur-Yvette - France)
8CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon - 14 rue Paul Gaffarel - 21079 Dijon - France)
9I2M - Institut de Mathématiques de Marseille (Centre de Mathématiques et Informatique (CMI) Technopôle Château-Gombert 39, rue Frédéric Joliot Curie 13453 Marseille Cedex 13 - France)
10Service d'hématologie clinique (Créteil - France)
11UPEC Médecine - Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (8, rue du Général Sarrail - 94010 Créteil Cedex - France)
12CHU Saint-Antoine [AP-HP] (184, rue du Faubourg Saint-Antoine 75571 Paris cedex 12 - France)
13Baobab [LBBE] (LBBE 43 Bld du 11 Novembre 1918 69622 VILLEURBANNE CEDEX - France)
14ERABLE - Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (Université Claude Bernard (Lyon 1), Campus DOUA 43, Boulevard du 11 Novembre 1918 69622 Villeurbanne cedex - France)

Tóm tắt

Abstract

The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations inEZH2have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role ofEZH2genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles ofEZH2were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in theEZH2gene (mutationn=46, gainn=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate forEZH2mutation analysis. However, this score did not predict the presence of gains at theEZH2locus. The presence of anEZH2genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36–0.93,P=0.025). We propose that the copy-number status ofEZH2should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.

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