Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas.
Programmed death ligands (PDLs) are immune-regulatory molecules that are frequently affected by chromosomal alterations in B-cell lymphomas. Although PDL copy-number variations are well characterized, a detailed and comprehensive analysis of structural rearrangements (SRs) and associated phenotypic consequences is largely lacking. Here, we used oligonucleotide capture sequencing of 67 formalin-fixed paraffin-embedded tissues derived from primary B-cell lymphomas and 1 cell line to detect and characterize, at base-pair resolution, SRs of the PDL locus (9p24.1; harboring PDL1/CD274 and PDL2/PDCD1LG2). We describe 36 novel PDL SRs, including 17 intrachromosomal events (inversions, duplications, deletions) and 19 translocations involving BZRAP-AS1, CD44, GET4, IL4R, KIAA0226L, MID1, RCC1, PTPN1 and segments of the immunoglobulin loci. Moreover, analysis of the precise chromosomal breakpoints reveals 2 distinct cluster breakpoint regions (CBRs) within either CD274 (CBR1) or PDCD1LG2 (CBR2). To determine the phenotypic consequences of these SRs, we performed immunohistochemistry for CD274 and PDCD1LG2 on primary pretreatment biopsies and found that PDL SRs are significantly associated with PDL protein expression. Finally, stable ectopic expression of wild-type PDCD1LG2 and the PDCD1LG2-IGHV7-81 fusion showed, in coculture, significantly reduced T-cell activation. Taken together, our data demonstrate the complementary utility of fluorescence in situ hybridization and capture sequencing approaches and provide a classification scheme for PDL SRs with implications for future studies using PDL immune-checkpoint inhibitors in B-cell lymphomas.
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada; Bioinformatics Training Program, and.
Lauren C
LC
Chong
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada;
David D W
DD
Twa
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada;
Anja
A
Mottok
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Susana
S
Ben-Neriah
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Bruce W
BW
Woolcock
Canada's Michael Smith Genome Sciences Centre, Vancouver, BC, Canada;
Yongjun
Y
Zhao
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Kerry J
KJ
Savage
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada; Canada's Michael Smith Genome Sciences Centre, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; and.
Marco A
MA
Marra
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
David W
DW
Scott
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada;
Randy D
RD
Gascoyne
Canada's Michael Smith Genome Sciences Centre, Vancouver, BC, Canada; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
Ryan D
RD
Morin
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada; Canada's Michael Smith Genome Sciences Centre, Vancouver, BC, Canada;
Andrew J
AJ
Mungall
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada;
Christian
C
Steidl
D060890:B7-H1 Antigen / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics* / Q000276:immunology; D005260:Female; D056426:Genetic Loci; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology; D008297:Male; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics* / Q000276:immunology
D060890:B7-H1 Antigen; C423236:CD274 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein