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

  • Chapuy B
  • Roemer M
  • Stewart C
 et al. 
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Introduction. Primary testicular lymphoma (PTL) and primary central nervous system lymphoma (PCNSL) are large B-cell lymphomas (LBCL) that occur in immune privileged (IP) sites and share certain clinical and molecular features. To date, the treatment of these IP lymphomas is largely empiric and more effective targeted therapies are needed.

Methods. To define actionable genetic features of IP lymphomas, we performed comprehensive genomic analyses of 21 PCNSLs and 7 PTLs and validated specific alterations in an independent cohort of 43 additional PTLs. Recurrent copy number alterations (CNAs) were detected using high-density single nucleotide polymorphism (SNP) arrays and the GISTIC algorithm and integrated with transcriptional profiles to identify candidate driver genes. Recurrent somatic mutations were identified using a combination of whole exome sequencing (WES) of paired tumor/normal samples and whole transcriptome sequencing (RNA-Seq) of the additional tumors without paired normal samples.

Results. In systemic diffuse large B-cell lymphomas (DLBCLs), multiple low-frequency CNAs and associated target genes decrease p53 activity and perturb cell cycle regulation; infrequent somatic mutations of TP53 also deregulate these pathways (Cancer Cell, 2012; 22:359-372). In contrast, PCNSLs and PTLs primarily exhibit bi-allelic deletion of the upstream regulator of p53 activity and cell cycle, CDKN2A (~70% PCNSLs and ~80% of PTLs) and rarely have copy loss or somatic mutations of TP53 or CNAs of additional pathway components.

The most commonly mutated genes in PCNSL and PTL, CD79B and MYD88 , are also perturbed in a subset of systemic DLBCLs. However, mutations of these two genes are much more frequent in IP lymphomas (70% MYD88 and 61% CD79B of analyzed PCNSLs and PTLs) and these alterations are commonly found in the same cases (57% of cases in this series). These data indicate that concurrent oncogenic activation of the B-cell receptor (BCR) and the Toll-like receptor (TLR) signaling pathways is a characteristic feature of IP lymphomas with implications for targeted therapies.

Among the IP lymphomas, ~20% of PCNSLs and ~40% PTLs exhibit 3q12.3/ NF K BIZ copy gain and increased expression of the NFKBIZ protein product, IκB-ζ, an atypical IκB family member induced by TLR signaling. In our PTL series, MYD88 wild-type tumors had the highest 3q12.3/ NFKBIZ copy gains, and ~90% of all analyzed PTLs had structural bases for NFκB activation via the TLR pathway. Lentiviral-mediated IκB-ζ knockdown decreased expression of the IκB-ζ target genes, IκB-α and BCL-xL, and induced apoptosis of LBCL cell lines with MYD88 L265P mutations, NFKBIZ gain or both alterations. In addition, enforced expression of NFKBIZ enhanced the growth of LBCLs with normal NFKBIZ copy numbers. Taken together, these data suggest that many IP lymphomas depend upon oncogenic MYD88/NFKBIZ signaling.

Although the majority of CNAs and somatic mutations were shared by PCNSLs and PTLs, certain alterations were primarily observed in PTL. In both the initial and independent validation series, > 40% of PTLs exhibited copy gain of chromosome 9p24.1/ CD274 ( PD-L1 ) / PDCD1LG2 ( PD-L2 ) and associated overexpression of the PD-1 ligands. These observations were of particular interest because 9p24.1 copy gain is a characteristic abnormality in two additional lymphoid malignancies, primary mediastinal LBCL and classical Hodgkin lymphoma, PD-1 signaling promotes tumor immune evasion and the PD-1 pathway is targetable. We also identified one PTL in which a novel translocation juxtaposed the regulatory elements of TBL1XR1 (chromosome 3) to the start codon-bearing exon 2 of PDCD1LG2 ( PD-L2 ) (chromosome 9). This translocation, which was detected by RNA-Seq and confirmed by 5’ RACE and a newly developed split-apart FISH assay, resulted in dramatic overexpression of the PD-L2 protein. These data suggest that PTLs utilize several genetic mechanisms to deregulate the PD-1 ligands and limit anti-tumor immunity.

Conclusions. Integrative and comparative genomic studies define PCNSL and PTL as related but unique lymphoid malignancies with targetable genetic alterations, and associated p53 deficiency and cell cycle deregulation, concurrent oncogenic BCR and TLR signaling and PD-1 dependent immune evasion that warrant further clinical investigation.

Note: B.C. and M.G.M.R have made equal contributions to this research.

Disclosures Feuerhake: Roche Pharma Research and Early Development (pRED) from 2008-2012: Employment. Freeman: Merck: on the PD-1 pathway Patents & Royalties; EMD-Serrono: on the PD-1 pathway Patents & Royalties; Boehringer-Ingelheim: on the PD-1 pathway Patents & Royalties; Amplimmune: on the PD-1 pathway Patents & Royalties; Roche: on the PD-1 pathway Patents & Royalties; Bristol-Myers-Squibb: on the PD-1 pathway Patents & Royalties; Novatis: on the PD-1 pathway, on the PD-1 pathway Patents & Royalties. Shipp: Sanofi: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Membership on an entity's Board of Directors or advisory committees.

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  • Bjoern Chapuy

  • Margaretha G.M. Roemer

  • Chip Stewart

  • Yuxiang Tan

  • Ryan P. Abo

  • Liye Zhang

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