ID
45371
Description
Principal Investigator: Margaret A Shipp, Dana Farber Cancer Institute, Boston MA, USA MeSH: Hodgkin Disease https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000450 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 EBVsup+/sup 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-KB, JAK/STAT and PI3K signaling pathways. EBV- cHLs had a higher prevalence of genetic alterations in the NF-KB 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 manuscriptsup1/sup). Reprinted from *Blood Advances* 2019;3(23):4065-4080.PMID: 31816062.
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- 11/4/22 11/4/22 - Chiara Middel
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Margaret A Shipp, Dana Farber Cancer Institute, Boston MA, USA
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November 4, 2022
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Creative Commons BY 4.0
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dbGaP phs000450 Genomic Analyses of Flow-sorted Hodgkin Reed Sternberg Cells Reveal Complementary Mechanisms of Immune Evasion.
Subject ID and consent group of subjects affected with diffuse large B-cell lymphoma and involved in the "Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma" project.
- StudyEvent: SEV1
- Eligibility Criteria
- Sample ID, subject ID, and sample use variables associated with participants affected with diffuse large B-cell lymphoma and involved in the "Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma" project.
- Subject ID, age, gender, and primary diagnosis of participants affected with diffuse large B-cell lymphoma and involved in the "Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma" project.
- Sample ID, analyte type [DNA], tumor status, and hospital diagnosis of samples obtained from participants with diffuse large B-cell lymphoma and involved in the "Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma" project.
- Subject ID and consent group of subjects affected with diffuse large B-cell lymphoma and involved in the "Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma" project.
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Subject ID and consent group of subjects affected with diffuse large B-cell lymphoma and involved in the "Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma" project.
- StudyEvent: SEV1
- Eligibility Criteria
- Sample ID, subject ID, and sample use variables associated with participants affected with diffuse large B-cell lymphoma and involved in the "Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma" project.
- Subject ID, age, gender, and primary diagnosis of participants affected with diffuse large B-cell lymphoma and involved in the "Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma" project.
- Sample ID, analyte type [DNA], tumor status, and hospital diagnosis of samples obtained from participants with diffuse large B-cell lymphoma and involved in the "Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma" project.
- Subject ID and consent group of subjects affected with diffuse large B-cell lymphoma and involved in the "Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma" project.
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