Genetic alterations of NK/T-cell lymphoma

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dc.description학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2017. 2. 김종일.-
dc.description.abstractIntroduction: 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.

Methods: To investigate the ENKL-specific genetic variants, 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).

Results: 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.

Conclusions: 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.
dc.description.tableofcontentsIntroduction 1
Extranodal NK/T-cell lymphoma nasal type (ENKL) 1
Genetic variations of ENKL in previous studies 1
Genomic sequencing in cancer study 2
Purpose and design of study 3
Material and Methods 4
NGS study subjects 4
DNA and RNA sequencing 6
Sequence variation analysis 9
Fusion gene analysis 9
Gene expression profiles of ENKL 10
Results 12
ENKL samples exhibited genomic heterogeneity and frequent mutations in TSGs 12
Genome analysis of ENKL revealed enrichment of alterations in the JAK/STAT pathway, among which STAT3 was the most frequently mutated gene 17
Mutations in MLL2 and BCOR, which are related to epigenetic regulation, were also frequent in ENKL 21
RNA-Seq revealed novel fusion genes and inactivation of BCOR as driver candidates 22
The gene expression profiles of both ENKL tissues and cell line samples reflect JAK/STAT cascade dysregulation and epigenetic alteration 26
Cancer tissue-specific DEGs are linked to the pathophysiologic features of ENKL 34
Discussion 36
References 44
Abstract in Korean 53
dc.format.extent934409 bytes-
dc.publisher서울대학교 대학원-
dc.subjectextranodal NK/T-cell lymphoma nasal type-
dc.subjectnext-generation sequencing-
dc.subjectJAK-STAT pathway-
dc.subjectchromatin modification-
dc.subjectsomatic mutation-
dc.titleGenetic alterations of NK/T-cell lymphoma-
dc.contributor.affiliation의과대학 의과학과-
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biomedical Sciences (대학원 의과학과)Theses (Ph.D. / Sc.D._의과학과)
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