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

Abstract

Key Points PCNSLs and PTLs have a defining genetic signature that differs from other LBCLs and suggests rational targeted therapies. PCNSLs and PTLs frequently exhibit 9p24.1/PD-L1/PD-L2 copy number alterations and translocations, likely genetic bases of immune evasion.

Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas

“…[5][6][7]16 Collectively, these data provide the basis for categorizing such translocations and intrachromosomal SRs into 4 distinct subgroups: CBR1, CBR2, nonclustered translocations, and intrachromosomal SRs. Here, we show that translocations arising in CBR2 are the most common (13 total reported events) followed by those arising in CBR1 (7 total reported events).…”

“…These events add to 6 intrachromosomal rearrangements that have been previously observed in immune-privilege lymphomas. 7,16,23 The functional effects of these rearrangements on both PDLs by IHC suggest that an increase in ligand expression is achieved through deletion of 39 UTRs and duplications of 1 or both PDL genes. 7 Our coculturing experiments using engineered cells, which are representative of duplications (wild-type PDCD1LG2-expressing DOHH-2) and 39 deletions (PDCD1LG2-IGHV7-81-expressing DOHH-2 cells, because this fusion results in the loss of the 2 terminal 39 PDCD1LG2 exons), provide additional support for this observation.…”

The emerging role of immune checkpoint inhibition in malignant lymphoma

“…The aforementioned 9p24.1 alterations responsible for PD-L1/L2 upregulation in cHL have also been observed in specific subsets of large B-cell lymphoma such as primary mediastinal but also primary testicular lymphoma and primary central nervous system DLBCL. [42][43][44] Furthermore, the PD-L1/PD-L2 locus was identified as a recurrent translocation partner for immunoglobulin heavy chain locus, a hallmark of DLBCL, by whole genome sequencing analysis. Interestingly, these cytogenetic alterations were more frequently observed in the non-germinal center B-cell-like type of DLBCL.…”

PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma

“…[1][2][3][4][5] PCNSLs arise from the brain, spinal cord, leptomeninges, or eye in the absence of prior or concurrent systemic disease. The median overall survival of patients with PCNSL is 30 to 50 months, with recurrence rates of almost 50% within the first 2 years of diagnosis.…”