Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type

Abstract

Cutaneous diffuse large B-cell lymphomas (DLBCLs) are aggressive lymphomas with a poor prognosis. To elucidate their genetic bases, we analyzed exome sequencing of 37 cutaneous DLBCLs, including 31 DLBCLs, leg type (DLBCL-LT) and 6 cutaneous DLBCLs-not otherwise specified (DLBCL-NOS). As reported previously, 77% of DLBCL-LT harbor NF-κB-activating MYD88 mutations. In nearly all MYD88-wild-type DLBCL-LT, we found cancer-promoting mutations that either activate the NF-κB pathway through alternative genes (NFKBIE or REL) or activate other canonical cancer pathways (BRAF, MED12, PIK3R1, and STAT3). After NF-κB, the second most commonly mutated pathway putatively enables immune evasion via mutations predicted to downregulate antigen processing (B2M, CIITA, HLA) or T-cell co-stimulation (CD58). DLBCL-LT have little genetic overlap with the genetically heterogeneous DLBCL-NOS. Instead, they resemble primary central nervous system and testicular large B-cell lymphomas (primary central nervous system lymphomas and primary testicular lymphomas). Like primary central nervous system lymphomas/primary testicular lymphomas, 40% of DLBCL-LT (vs. 0% of DLBCLs-not otherwise specified) harbored PDL1/PDL2 translocations, which lead to overexpression of PD-L1 or PD-L2 in 50% of the cases. Collectively, these data broaden our understanding of cutaneous DLBCLs and suggest novel therapeutic approaches (e.g., BRAF or PI3K inhibitors). Additionally, they suggest novel treatment paradigms, wherein DLBCL-LT can be targeted with strategies (e.g., immune checkpoint blockers) currently being developed for genomically similar primary central nervous system lymphomas/primary testicular lymphomas.

Primary cutaneous diffuse large B‐cell lymphoma, NOS and leg type: Clinical, morphologic and prognostic differences

“…While this aspect did not correlate with a better outcome in the total PCLBCL cohort, it differed significantly between BCL‐2 + PCLBCL/LT and BCL‐2 – PCLBCL/NOS, and one could therefore speculate that an anti‐tumor immune reaction contributes to the differences in clinical presentation and outcome between PCLBCL/NOS and PCLBCL/LT. This hypothesis is supported by a recent publication by Zhou et al., where they show that genomic alterations in PCLBCL/NOS favor an immune evasion of the tumor cells .…”

“…Recent analyses show that the genomes of PCLBCL/LT and PCLBCL/NOS are different, e.g. with activating MYD88 mutations in PCLBCL/LT . Genomic studies may therefore be helpful in future.…”

Primär kutanes diffus‐großzelliges B‐Zell‐Lymphom, NOS oder leg type: klinische, morphologische und prognostische Unterschiede

“…Diese Hypothese wird durch eine neuere Publikation von Zhou et al. gestützt, in der die Autoren zeigten, dass Genomveränderungen bei PCLBCL/NOS eine Immunevasion der Tumorzellen begünstigt .…”

“…Aktuelle Analysen zeigen, dass es zwischen PCLBCL/LT und PCLBCL/NOS genomische Unterschiede gibt. So treten beispielsweise bei PCLBCL/LT aktivierende Mutationen von MYD88 auf . Genomische Analysen an größeren Fallkollektiven könnten somit möglicherweise zu einer verlässlicheren Subklassifikation beitragen.…”

Rituximab, lenalidomide and pembrolizumab in refractory primary cutaneous diffuse large B‐cell lymphoma, leg type

“…Fluorescence in situ hybridisation analysis was positive for MYC gene locus rearrangement (Schrader et al, 2018;Zhou et al, 2018) and revealed clonal copy number gains of MYC and BCL2. Monoclonal rearrangement of immunoglobulin heavy (IGH) chain was found and mutational analysis revealed a KRAS point mutation p.A146V, but MYD88 was not mutated (Mareschal et al, 2017).…”