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

Xiaolong Alan Zhou, Abner Louissaint, Alexander Wenzel, Jingyi Yang, Maria Estela Martinez-Escala, Andrea P. Moy, Elizabeth A. Morgan, Christian N. Paxton, Bo Hong, Erica F. Andersen, Joan Guitart, Amir Behdad, Lorenzo Cerroni, David M. Weinstock, Jaehyuk Choi*

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2365-2376
Number of pages12
JournalJournal of Investigative Dermatology
Volume138
Issue number11
DOIs
StatePublished - Nov 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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    Zhou, X. A., Louissaint, A., Wenzel, A., Yang, J., Martinez-Escala, M. E., Moy, A. P., Morgan, E. A., Paxton, C. N., Hong, B., Andersen, E. F., Guitart, J., Behdad, A., Cerroni, L., Weinstock, D. M., & Choi, J. (2018). Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type. Journal of Investigative Dermatology, 138(11), 2365-2376. https://doi.org/10.1016/j.jid.2018.04.038