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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.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
2
Harvard Medical School, Boston, MA.
3
Department of Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany.
4
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
5
Department of Laboratory Medicine, University of Washington, Seattle, WA.
6
Department of Data Science, Knowledge Systems Group, Boston, MA.
7
Center for Cancer Genome Discovery, Boston, MA.
8
Hematologic Neoplasia Flow Cytometry Core and.
9
Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA.
10
Department of Pathology, Brigham and Women's Hospital, Boston, MA; and.
11
Department of Pathology and.
12
Center for Cancer Research, Massachusetts General Hospital, Boston, MA.

Abstract

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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