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Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma

Anja Mottok, Stacy S. Hung, Elizabeth A. Chavez, Bruce Woolcock, Adèle Telenius, Lauren C. Chong, Barbara Meissner, Hisae Nakamura, Christopher Rushton, Elena Viganò, Clementine Sarkozy, Randy D. Gascoyne, Joseph M. Connors, Susana Ben Neriah, Andrew Mungall, Marco A. Marra, Reiner Siebert, David W. Scott, Kerry J. Savage and Christian Steidl

Key Points

  • Whole exome sequencing and gene expression profiling reveal genetic driver alterations and elucidate pathway dependencies in PMBL

  • Comparative analysis points to relevant differences to DLBCL and highlights the pathological and molecularly relatedness to cHL

Abstract

Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provided further insights into genotype-phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the JAK-STAT and NF-kB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, PDCD1LG2). Our analyses highlight the IRF-pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, IRF8). In addition, our integrative analysis illustrates the importance of JAK1,RELB and EP300mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL as compared to diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relationship between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic work-up and therapeutic decision-making.

  • Submitted April 14, 2019.
  • Revision received July 9, 2019.
  • Accepted June 28, 2019.