Genomic Analyses of Flow-sorted Hodgkin Reed Sternberg Cells Reveal Complementary Mechanisms of Immune Evasion.
UID: 10738
- Description
- Study Description from dbGaP: "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 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 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 NF-κB, JAK/STAT and PI3K signaling pathways. EBV- cHLs had a higher prevalence of genetic alterations in the NF-κB and MHC class I antigen presentation pathways. In this young cHL cohort (median age of 26), we identified a predominant mutational signature of spontaneous deamination of CpGs ("Aging"), in addition to APOBEC, AID and 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, 6q23.2 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 (companion manuscript1). Reprinted from Blood Advances 2019;3(23):4065-4080.PMID: 31816062. "
Diffuse Large B-Cell Lymphoma, NOS
Hodgkin Lymphoma
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Access via dbGaP
478 WXS sequencing run from 324 phenotyped subjects
Accession #: phs000450.v4.p1 - Access Restrictions
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Application Required
- Access Instructions
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- Data Type
- Equipment Used
- Software Used
- Dataset Format(s)
- SRA, BAM
- Data Tool(s)
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WXS
- Dataset Size
- 1.81 TB
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