title: Recurrent genomic rearrangements in primary testicular lymphoma.
abstract: Primary testicular diffuse large B cell lymphoma (PTL) is an aggressive malignancy that occurs in the immune-privileged anatomical site of the testis. We have previously shown that structural genomic rearrangements involving the MHC class II transactivator CIITA and programmed death ligands (PDLs) 1 and 2 are frequent across multiple B cell lymphoma entities. Specifically in PTL, we found rearrangements in the PDL locus by fluorescence in situ hybridization (FISH). However, breakpoint anatomy and rearrangement partners were undetermined, while CIITA rearrangements had not been reported previously in PTL. Here, we performed bacterial artificial chromosome capture sequencing on three archival, formalin-fixed, paraffin-embedded tissue biopsies, interrogating 20 known rearrangement hotspots in B cell lymphomas. We report novel CIITA, FOXP1 and PDL rearrangements involving IGHG4, FLJ45248, RFX3, SMARCA2 and SNX29. Moreover, we present immunohistochemistry data supporting the association between PDL rearrangements and increased protein expression. Finally, using FISH, we show that CIITA (8/82; 10%) and FOXP1 (5/74; 7%) rearrangements are recurrent in PTL. In summary, we describe rearrangement frequencies and novel rearrangement partners of the CIITA, FOXP1 and PDL loci at base-pair resolution in a rare, aggressive lymphoma. Our data suggest immune-checkpoint inhibitor therapy as a promising intervention for PTL patients harbouring PDL rearrangements.
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: David D W
authors.initials: DD
authors.lastname: Twa
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.|Bioinformatics Training Programme, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Fong Chun
authors.initials: FC
authors.lastname: Chan
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Susana
authors.initials: S
authors.lastname: Ben-Neriah
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Woolcock
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: King L
authors.initials: KL
authors.lastname: Tan
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.|Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: McDonald
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Lim
authors.affiliation: Deeley Research Centre, BC Cancer Agency, Victoria, BC, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Brad H
authors.initials: BH
authors.lastname: Nelson
authors.affiliation: Deeley Research Centre, BC Cancer Agency, Victoria, BC, Canada.
authors.forename: Katy
authors.initials: K
authors.lastname: Milne
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.|Bioinformatics Training Programme, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.|Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, BC, Canada.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.|Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics*; D056905:Chromosome Breakpoints; D022202:Chromosomes, Artificial, Bacterial; D051858:Forkhead Transcription Factors / Q000235:genetics*; D017353:Gene Deletion; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics*; D012008:Recurrence; D012097:Repressor Proteins / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D012097:Repressor Proteins; D015534:Trans-Activators
keywords: CD274; CIITA; FOXP1; PDCD1LG2; capture sequencing; fluorescence in situ hybridization (FISH); genomic rearrangements; primary testicular lymphoma (PTL); programmed death ligands