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Blood Adv. 2019 Dec 10;3(23):4065-4080. doi: 10.1182/bloodadvances.2019001012.

Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion.

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Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
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 Laboratory Medicine, University of Washington, Seattle, WA.
Department of Data Science, Knowledge Systems Group, Boston, MA.
Center for Cancer Genome Discovery, Boston, MA.
Hematologic Neoplasia Flow Cytometry Core and.
Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA.
Department of Pathology, Brigham and Women's Hospital, Boston, MA; and.
Department of Pathology and.
Center for Cancer Research, Massachusetts General Hospital, Boston, MA.


Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands. To define genetic mechanisms of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole-exome sequencing of flow cytometry-sorted HRS cells from 23 excisional biopsies of newly diagnosed cHLs, including 8 Epstein-Barr virus-positive (EBV+) tumors. We identified significantly mutated cancer candidate genes (CCGs) as well as somatic copy number alterations and structural variations and characterized their contribution to disease-defining immune evasion mechanisms and nuclear factor κB (NF-κB), JAK/STAT, and PI3K signaling pathways. EBV- cHLs had a higher prevalence of genetic alterations in the NF-κB and major histocompatibility complex class I antigen presentation pathways. In this young cHL cohort (median age, 26 years), we identified a predominant mutational signature of spontaneous deamination of cytosine- phosphate-guanines ("Aging"), in addition to apolipoprotein B mRNA editing catalytic polypeptide-like, activation-induced cytidine deaminase, and microsatellite instability (MSI)-associated hypermutation. In particular, the mutational burden in EBV- cHLs was among the highest reported, similar to that of carcinogen-induced tumors. Together, the overall high mutational burden, MSI-associated hypermutation, and newly identified genetic alterations represent additional potential bases for the efficacy of PD-1 blockade in cHL. Of note, recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1 mutations and 2p/2p15, 6p21.32, 6q23.3, and 9p/9p24.1 copy number alterations, were also identified in >20% of primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases.

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