PF519 MOLECULAR PROFILING OF PRIMARY BONE LYMPHOMA'S REVEALS FREQUENT MUTATIONS IN EZH2 AND OTHER EPIGENETIC GENES: IMPLICATIONS FOR TARGETED TREATMENT
Authors: Ibramoglu∗ M. Suleiman , de Groen∗ R.A. , van Eijk R. , van Wezel T. , Raghoo R. , de Winter E.R. , Schrader A.M. , Jansen P.M. , Bruijn I. Briaire‐de , Kleiverda K. , Vlasveld L. , Posthuma W.F. , van den Berg A. , Diepstra A. , Lugtenburg P.J. , Bovée J.V. , Cleven∗ A.H. , Vermaat∗ J.S. 
Published: June 2019

Background:Primary bone diffuse large B‐cell lymphoma (PB‐DLBCL) is a rare extranodal lymphoma comprising 1–2% of all malignant lymphomas. Large next‐generation sequencing (NGS) studies identified genetic drivers in nodal diffuse large B‐cell lymphomas (DLBCLs), resulting in novel targeted therapeutic opportunities. However, the genetic constitution of PB‐DLBCL is still unclear and extensive sequencing studies have yet been performed.Aims:We aim to determine mutational profiles in a unique large cohort of PB‐DLBCL patients in correlation with clinicopathological characteristics.Methods:This retrospective cohort study consisted of 38 patients with bone localization of DLBCL, of which pretreatment fresh frozen or formalin‐fixed paraffin‐embedded bone tissue samples were available. Patients were diagnosed between 2003 and 2019 at Leiden University Medical Center (LUMC), a center of expertise for bone tumors, and affiliated hospitals in the Netherlands. Strict definitions, based on radiological assessment of anatomical disease localizations at diagnosis were applied, categorizing 3 different subgroups (figure 1A): patients with osseous involvement only (single or multiple bone lesions) (PB‐DLBCL), patients with osseous involvement and locoregional lymphadenopathy (locoregional disease), and patients with osseous and multiple extraosseous localizations (disseminated disease). An in‐house developed and validated targeted NGS panel comprising 52 B‐cell lymphoma‐specific genes was used for sequencing with the Ion S5TM System.Results:Our cohort contained 38 patients, 22 (58%) were male, and the median age at diagnosis was 61 years (range 13–92). Twenty patients had PB‐DLBCL (53%), 4 had locoregional disease (10%), and 14 had disseminated disease (37%). NGS analysis identified 32 genes with ‘pathogenic’ mutations, with on average 2.3 mutated genes per patient (figure 1B). No mutations were detected in 4 patients with disseminated disease. Overall, in patients with bone localization of DLBCL, high mutation frequencies were observed for EZH2 (31.6%), TP53 (21.1%), B2 M (15.8%), and TNFRSF14 (15.8%), belonging to epigenetic (63.2%), DNA damage response (21.1%), and immunity (26.3%) pathways, respectively. In PB‐DLBCL, EZH2 (35%) and TP53 (25%) mutations were considerably more frequently detected compared to disseminated disease (21% and 14%, respectively). In context, previous studies reported substantial lower incidences of mutated EZH2 (11–22%) and TP53 (12–20%) in DLBCLs with germinal center B‐cell (GCB) subtype (Reddy A. et al. 2017; Karube K. et al. 2018; Schmitz R. et al. 2018; and Chapuy B. et al. 2018). Although a small patient group, locoregional disease also demonstrated frequent mutations in EZH2 (50%, 2/4), TNFRSF14 (50%, 2/4), B2 M (50%, 2/4), and TP53 (25%, 1/4).Taken together, these findings demonstrate that the epigenetic pathway is affected most commonly in PB‐DLBCL and locoregional disease (75%), with a substantial lower frequency in disseminated disease (43%) (figure 1C). Correlation of genetic aberrations with gene‐expression profiling and clinicopathological characteristics will follow shortly.Summary/Conclusion:To our knowledge, this is the first study reporting a higher frequency of epigenetic mutations in patients with bone localization of DLBCL, thereby strengthening the concept that DLBCLs with bone location belong to the GCB subtype. Furthermore, the high incidence of mutated EZH2 in PB‐DLBCL patients provides a rationale for exploration of novel targeted treatment with EZH2 inhibitors to improve survival outcomes in these patients.image