Whole-exome and transcriptome sequencing of refractory diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although rituximab therapy improves clinical outcome, some patients develop resistant DLBCL; however, the genetic alterations in these patients are not well documented. To identify the genetic background of refractory DLBCL, we conducted whole-exome sequencing and transcriptome sequencing for six patients with refractory and seven with responsive DLBCL. The average numbers of pathogenic somatic single nucleotide variants and indels in coding regions were 71 in refractory patients (range 28-120) and 38 (range 19-66) in responsive patients. Missense mutations of TP53 were exclusive in 50% (3/6) of refractory patients and involved the DNA-binding domain of TP53. All missense mutations of TP53 were accompanied by copy number deletions. RAB11FIP5, PRKCB, PRDM15, FNBP4, AHR, CEP128, BRE, DHX16, MYO6, and NMT1 mutations were recurrent in refractory patients. MYD88, B2M, SORCS3, and WDFY3 mutations were more frequent in refractory patients than in responsive patients. REL-BCL11A fusion was found in two refractory patients; one had both fusion and copy number gain. Recurrent copy gains of POU2AF1, SLC1A4, REL11, FANCL, CACNA1D, TRRAP, and CUX1 with significantly increased average expression were found in refractory patients. The expression profile revealed enriched gene sets associated with treatment resistance, including oxidative phosphorylation and ATP-binding cassette transporters. In conclusion, this study integrated both genomic and transcriptomic alterations associated with refractory DLBCL and found several treatment-resistance alterations that may contribute to refractoriness.
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Republic of Korea.|Department of Pathology, Samsung Medical Center, SungKyunKwan University, Seoul, 06351, Republic of Korea.
Ha Young
HY
Park
Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, 03080, Republic of Korea.
Seung-Bok
SB
Lee
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, Republic of Korea.
Hae-Yong
HY
Yoo
Section of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sung Kyun Kwan University, 06351, Republic of Korea.
Seok-Jin
SJ
Kim
Section of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sung Kyun Kwan University, 06351, Republic of Korea.
Won-Seog
WS
Kim
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Republic of Korea.
Jong-Il
JI
Kim
Department of Pathology, Samsung Medical Center, SungKyunKwan University, Seoul, 06351, Republic of Korea.
Young-Hyeh
YH
Ko
D056915:DNA Copy Number Variations; D059472:Exome; D050939:Gene Fusion; D016158:Genes, p53; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D009154:Mutation; D059467:Transcriptome
diffuse large B cell lymphoma; refractory; sequencing; transcriptome; whole exome