The mutational landscape of ocular marginal zone lymphoma identifies frequent alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP.
Ocular marginal zone lymphoma is a common type of low-grade B-cell lymphoma. To investigate the genomic changes that occur in ocular marginal zone lymphoma, we analyzed 10 cases of ocular marginal zone lymphoma using whole-genome and RNA sequencing and an additional 38 cases using targeted sequencing. Major genetic alterations affecting genes involved in nuclear factor (NF)-κB pathway activation (60%), chromatin modification and transcriptional regulation (44%), and B-cell differentiation (23%) were identified. In whole-genome sequencing, the 6q23.3 region containing TNFAIP3 was deleted in 5 samples (50%). In addition, 5 structural variation breakpoints in the first intron of IL20RA located in the 6q23.3 region was found in 3 samples (30%). In targeted sequencing, a disruptive mutation of TNFAIP3 was the most common alteration (54%), followed by mutations of TBL1XR1 (18%), cAMP response element binding proteins (CREBBP) (17%) and KMT2D (6%). All TBL1XR1 mutations were located within the WD40 domain, and TBL1XR1 mutants transfected into 293T cells increased TBL1XR1 binding with nuclear receptor corepressor (NCoR), leading to increased degradation of NCoR and the activation of NF-κB and JUN target genes. This study confirms genes involving in the activation of the NF-kB signaling pathway is the major driver in the oncogenesis of ocular MZL.
Samsung Genome Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.|Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Hyunchul
H
Jung
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
Hae Yong
HY
Yoo
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
Seung Ho
SH
Lee
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Sohyun
S
Shin
Samsung Genome Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.
Sang Cheol
SC
Kim
Samsung Genome Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.
Sejoon
S
Lee
Samsung Genome Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.
Je-Gun
JG
Joung
Samsung Genome Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.|Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
Jae-Yong
JY
Nam
Samsung Genome Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.|Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
Daeun
D
Ryu
Samsung Genome Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.|Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Jae Won
JW
Yun
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Jung Kyoon
JK
Choi
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Ambarnil
A
Ghosh
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Kyeong Kyu
KK
Kim
Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Seok Jin
SJ
Kim
Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Won Seog
WS
Kim
Samsung Genome Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.
Woong-Yang
WY
Park
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Young Hyeh
YH
Ko
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050882:CREB-Binding Protein / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005134:Eye Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D015151:Immunoblotting; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics* / Q000378:metabolism
D016328:NF-kappa B; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C473691:TBL1XR1 protein, human; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
RNA sequencing; marginal zone lymphoma; mutation; ocular; whole-genome sequencing