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

9 Citations (Scopus)

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

Fingerprint

Immune Evasion
Lymphoma, Large B-Cell, Diffuse
Neurology
Leg
Genes
Cells
Lymphoma
T-cells
Central Nervous System
Ports and harbors
Phosphatidylinositol 3-Kinases
Skin
B-Cell Lymphoma
Mutation
Antigens
Processing
Exome
Antigen Presentation
Neoplasms
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Zhou, Xiaolong Alan ; Louissaint, Abner ; Wenzel, Alexander ; Yang, Jingyi ; Martinez-Escala, Maria Estela ; Moy, Andrea P. ; Morgan, Elizabeth A. ; Paxton, Christian N. ; Hong, Bo ; Andersen, Erica F. ; Guitart, Joan ; Behdad, Amir ; Cerroni, Lorenzo ; Weinstock, David M. ; Choi, Jaehyuk. / Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type. In: Journal of Investigative Dermatology. 2018 ; Vol. 138, No. 11. pp. 2365-2376.
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title = "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.",
author = "Zhou, {Xiaolong Alan} and Abner Louissaint and Alexander Wenzel and Jingyi Yang and Martinez-Escala, {Maria Estela} and Moy, {Andrea P.} and Morgan, {Elizabeth A.} and Paxton, {Christian N.} and Bo Hong and Andersen, {Erica F.} and Joan Guitart and Amir Behdad and Lorenzo Cerroni and Weinstock, {David M.} and Jaehyuk Choi",
year = "2018",
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language = "English (US)",
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Zhou, XA, Louissaint, A, Wenzel, A, Yang, J, Martinez-Escala, ME, Moy, AP, Morgan, EA, Paxton, CN, Hong, B, Andersen, EF, Guitart, J, Behdad, A, Cerroni, L, Weinstock, DM & Choi, J 2018, 'Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type', Journal of Investigative Dermatology, vol. 138, no. 11, pp. 2365-2376. https://doi.org/10.1016/j.jid.2018.04.038

Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type. / Zhou, Xiaolong Alan; Louissaint, Abner; Wenzel, Alexander; Yang, Jingyi; Martinez-Escala, Maria Estela; Moy, Andrea P.; Morgan, Elizabeth A.; Paxton, Christian N.; Hong, Bo; Andersen, Erica F.; Guitart, Joan; Behdad, Amir; Cerroni, Lorenzo; Weinstock, David M.; Choi, Jaehyuk.

In: Journal of Investigative Dermatology, Vol. 138, No. 11, 11.2018, p. 2365-2376.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type

AU - Zhou, Xiaolong Alan

AU - Louissaint, Abner

AU - Wenzel, Alexander

AU - Yang, Jingyi

AU - Martinez-Escala, Maria Estela

AU - Moy, Andrea P.

AU - Morgan, Elizabeth A.

AU - Paxton, Christian N.

AU - Hong, Bo

AU - Andersen, Erica F.

AU - Guitart, Joan

AU - Behdad, Amir

AU - Cerroni, Lorenzo

AU - Weinstock, David M.

AU - Choi, Jaehyuk

PY - 2018/11

Y1 - 2018/11

N2 - 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.

AB - 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.

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