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Blood. 2016 Feb 18;127(7):869-81. doi: 10.1182/blood-2015-10-673236. Epub 2015 Dec 23.

Targetable genetic features of primary testicular and primary central nervous system lymphomas.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands;
3
Broad Institute, Cambridge, MA;
4
Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA;
5
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
6
Department of Pathology, Brigham and Women's Hospital, Boston, MA;
7
Center of Gynaecologic Oncology, VU University Medical Center, Amsterdam, The Netherlands;
8
Department of Pathology, Hannover Medical School, Hannover, Germany;
9
Department of Hematology and Oncology, University Hospital Freiburg, Freiburg, Germany;
10
Massachusetts General Hospital/North Shore Cancer Center, Danvers, MA;
11
Department of Pathology, Massachusetts General Hospital, Boston, MA; and.
12
Broad Institute, Cambridge, MA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
13
Broad Institute, Cambridge, MA; Department of Pathology, Massachusetts General Hospital, Boston, MA; and.
14
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands;

Abstract

Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL.

PMID:
26702065
PMCID:
PMC4760091
DOI:
10.1182/blood-2015-10-673236
[Indexed for MEDLINE]
Free PMC Article

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