S101: Genetic and Epigenetic Factors Driving Primary Mediastinal B-Cell Lymphoma Pathogenesis and Outcome

Abstract

Background: Background:Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive lymphoma affecting predominantly young female patients. Previous studies in this rare entity have focused on single genes or were limited in cohort size.

Frequent ZNF217 mutations lead to transcriptional deregulation of interferon signal transduction via altered chromatin accessibility in B cell lymphoma

“…This study included 157 previously untreated PMBCL patients from collaborating centers in 5 countries. Additional 83 samples with available RNA and known ZNF217 mutation status were studied [ 20 , 22 ] (Supplementary Table 1 ).…”

“…Based on published data and our ongoing genome/exome-wide sequencing studies (manuscript in preparation [ 20 ]), a designated panel of 106 genes targeting all coding regions was selected to generate a custom cRNA bait library (SureSelect, Agilent Technologies), which was used for targeted gene capture (Supplementary Table S2 ). In addition, a set of baits targeting common SNPs was designed to allow for copy-number calling.…”

“…To overcome the limitations associated with the lack of germline DNA, we developed rigorous filtering criteria by comparison of tumor-only targeted sequencing data with paired tumor-germline whole-exome sequencing data in 57 PMBCL cases that were investigated with both techniques. Cross-validation rates WES/TS for SNVs and SCNAs were: 97% and 93% [ 20 ]. This trained algorithm was thereafter applied to all tumor-only cases presented in the present study.…”

“…We and others recently reported recurrent mutations in the CoREST-binding protein ZNF217 in tumor samples from patients with primary mediastinal B cell lymphoma (PMBCL), gray zone lymphoma and Hodgkin lymphoma (HL) with the highest prevalence in PMBCL (~30%) [ 7 , 15 – 20 ]. ZNF217 , located on chromosome 20q13.2, has also been found among the 20 most frequently amplified genes in metastatic cancer [ 21 ].…”

Integrative genomic analysis identifies unique immune environments associated with immunotherapy response in diffuse large B cell lymphoma

“…We were particularly intrigued by the strong association between GCB hot DLBCLs and putative LoF SOCS1 mutations as SOCS1 is also frequently mutated in classical Hodgkin lymphoma (cHL) (48)(49)(50) and primary mediastinal B cell lymphoma (PMBL) (48,(51)(52)(53) -two lymphoma subtypes associated with inflamed immune environments and remarkable sensitivity to CBT (16,17,(54)(55)(56)(57). SOCS1 is a tumor suppressor and potent negative regulator of JAK/STAT signaling, and LoF mutations in SOCS1 have been implicated in enhancing oncogenic JAK/STAT signaling in lymphoma downstream of cytokines such as IL-4 and IL-13 (58)(59)(60)(61)(62).…”