Research Papers:

Whole-exome and transcriptome sequencing of refractory diffuse large B-cell lymphoma

Ha Young Park _, Seung-Bok Lee, Hae-Yong Yoo, Suk-Jin Kim, Won-Seog Kim, Jong-Il Kim and Young-Hyeh Ko

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Oncotarget. 2016; 7:86433-86445. https://doi.org/10.18632/oncotarget.13239

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Ha Young Park1,2, Seung-Bok Lee3, Hae-Yong Yoo4, Seok-Jin Kim5, Won-Seog Kim5, Jong-Il Kim1, Young-Hyeh Ko2

1Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Republic of Korea

2Department of Pathology, Samsung Medical Center, SungKyunKwan University, Seoul, 06351, Republic of Korea

3Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, 03080, Republic of Korea

4Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, Republic of Korea

5Section of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sung Kyun Kwan University, 06351, Republic of Korea

Correspondence to:

Young-Hyeh Ko, email: [email protected]

Jong-Il Kim, email: [email protected]

Keywords: diffuse large B cell lymphoma, refractory, whole exome, transcriptome, sequencing

Received: August 31, 2016     Accepted: October 28, 2016     Published: November 09, 2016


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. RELBCL11A 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.

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