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Blood. 2019 Dec 26;134(26):2369-2382. doi: 10.1182/blood.2019002067.

Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade.

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Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Department of Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany.
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Department of Data Sciences and.
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA; and.
Department of Pathology and.
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA.


Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, and molecular features with classical Hodgkin lymphoma (cHL), including constitutive activation of nuclear factor κB (NF-κB), JAK/STAT signaling, and programmed cell death protein 1 (PD-1)-mediated immune evasion. The demonstrated efficacy of PD-1 blockade in relapsed/refractory PMBLs led to recent approval by the US Food and Drug Administration and underscored the importance of characterizing targetable genetic vulnerabilities in this disease. Here, we report a comprehensive analysis of recurrent genetic alterations -somatic mutations, somatic copy number alterations, and structural variants-in a cohort of 37 newly diagnosed PMBLs. We identified a median of 9 genetic drivers per PMBL, including known and newly identified components of the JAK/STAT and NF-κB signaling pathways and frequent B2M alterations that limit major histocompatibility complex class I expression, as in cHL. PMBL also exhibited frequent, newly identified driver mutations in ZNF217 and an additional epigenetic modifier, EZH2. The majority of these alterations were clonal, which supports their role as early drivers. In PMBL, we identified several previously uncharacterized molecular features that may increase sensitivity to PD-1 blockade, including high tumor mutational burden, microsatellite instability, and an apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutational signature. The shared genetic features between PMBL and cHL provide a framework for analyzing the mechanism of action of PD-1 blockade in these related lymphoid malignancies.


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