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. 2015 Jul 10;6(19):17764-76.
doi: 10.18632/oncotarget.3776.

Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type

Seungbok Lee  1 , Ha Young Park  2 , So Young Kang  3 , Seok Jin Kim  4 , Jinha Hwang  2 , Seungho Lee  5 , Soo Heon Kwak  6 , Kyong Soo Park  6   7 , Hae Yong Yoo  5 , Won Seog Kim  4 , Jong-Il Kim  1   2   8 , Young Hyeh Ko  3
Affiliations

Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type

Seungbok Lee et al. Oncotarget. .

Abstract

Extranodal NK/T-cell lymphoma nasal type (ENKL) is a rare type of non-Hodgkin lymphoma that more frequently occurs in East Asia and Latin America. Even though its molecular background has been discussed in the last few years, the current knowledge does not explain the disease pathogenesis in most cases of ENKL. Here, we performed multiple types of next-generation sequencing on 34 ENKL samples, including whole-exome sequencing (9 cancer tissues and 4 cancer cell lines), targeted sequencing (21 cancer tissues), and RNA sequencing (3 cancer tissues and 4 cancer cell lines). Mutations were found most frequently in 3 genes, STAT3, BCOR, and MLL2 (which were present in 9, 7, and 6 cancer samples, respectively), whereas there were only 2 cases of JAK3 mutation. In total, JAK/STAT pathway- and histone modification-related genes accounted for 55.9% and 38.2% of cancer samples, respectively, and their involvement in ENKL pathogenesis was also supported by gene expression analysis. In addition, we provided 177 genes upregulated only in cancer tissues, which appear to be linked with angiocentric and angiodestructive growth of ENKL. In this study, we propose several novel driver genes of ENKL, and show that these genes and their functional groups may be future therapeutic targets of this disease.

Keywords: JAK-STAT pathway; chromatin modification; extranodal NK/T-cell lymphoma nasal type; next-generation sequencing; somatic mutation.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Distribution of mutations in ENKL
Figure 2
Figure 2. Locations of STAT3 mutations
All 9 missense SNVs were accumulated in the SH2 domain.
Figure 3
Figure 3. Functional enrichment of commonly upregulated or downregulated genes in both CT and CC samples
A. Hierarchical clustering and heat map of common DEGs. B. Gene ontologies enriched in up- or downregulated genes. C. Top 10 KEGG pathways and D. top 10 CGP gene sets enriched in upregulated genes.
Figure 4
Figure 4. Functional enrichment of genes that were upregulated only in CT samples
A. Gene ontologies enriched in CT-specific upregulated genes. There were several vasculature-development- or endothelium-development-related ontologies, which were the most significant. B. Top 10 KEGG pathways and C. top 10 CGP gene sets enriched in these genes.
Figure 5
Figure 5. Mutation rates of BCOR according to tumor type
EBV-associated malignancies (ENKL and EBV(+) GC) showed high percentages for both BCOR mutation rate and LOF proportion. LOF, loss-of-function; GC, gastric carcinoma; UECA, uterine endometrial carcinoma; LUAD, lung adenocarcinoma; CRC, colorectal adenocarcinoma; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.
See this image and copyright information in PMC

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