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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8405完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林淑華(Shu-Wha Lin) | |
| dc.contributor.author | Chih-Hsiang Yu | en |
| dc.contributor.author | 游智翔 | zh_TW |
| dc.date.accessioned | 2021-05-20T00:53:42Z | - |
| dc.date.available | 2022-08-01 | |
| dc.date.available | 2021-05-20T00:53:42Z | - |
| dc.date.copyright | 2020-09-03 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-07-28 | |
| dc.identifier.citation | 財團法人中華民國兒童癌症基金會, 財團法人中華民國兒童癌症基金會2018年度報告. 2019. 2. Pui, C.H., et al., Treating Childhood Acute Lymphoblastic Leukemia without Cranial Irradiation. New England Journal of Medicine, 2009. 360(26): p. 2730-2741. 3. Hunger, S.P. and C.G. Mullighan, Acute Lymphoblastic Leukemia in Children. New England Journal of Medicine, 2015. 373(16): p. 1541-1552. 4. Pui, C.H., K.E. Nichols, and J.J. Yang, Somatic and germline genomics in paediatric acute lymphoblastic leukaemia. Nature Reviews Clinical Oncology, 2019. 16(4): p. 227-240. 5. Heikamp, E.B. and C.H. Pui, Next-Generation Evaluation and Treatment of Pediatric Acute Lymphoblastic Leukemia. Journal of Pediatrics, 2018. 203: p. 14-24. 6. Ladetto, M., et al., Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia, 2014. 28(6): p. 1299-1307. 7. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8405 | - |
| dc.description.abstract | B細胞急性淋巴性白血病是最常見的兒童癌症。藉由危險分群導向的治療方案，其治療成績在過去幾十年間已有大幅度的進步。主要的預後相關危險因子包括了基因亞群例如非整倍體 (高二倍體或低二倍體)，融合基因，以及參與B細胞發育相關的基因突變，例如IKZF1及ERG基因等。近幾年來，數個研究團隊利用轉錄體定序對兒童B細胞急性淋巴性白血病進行全面性的研究，發現了數個具有獨特基因表達的新型基因亞群，且註明這些基因亞群也具有預後意義。為了進一步了解在台灣兒童的B細胞急性淋巴性白血病的基因變化，我利用多重連接依賴性探針擴增、DNA指數及反轉錄聚合酶連鎖反應分析常見的基因亞群在台灣的分布率，而未定出基因型的樣本則再以轉錄體定序偵測。藉由轉錄體定序，90%的B細胞急性淋巴性白血病皆可以被分類到特定的基因亞群。藉由與先前所發表的研究進行比較，我也發現了專屬於基因亞群的基因變化，例如在DUX4基因轉位急性淋巴性白血病中發現到高頻率的IKZF1及TP53基因突變，以及在ZNF384基因轉位急性淋巴性白血病發現高頻率的ETV6基因突變。另外也發現到台灣族群的B細胞急性淋巴性白血病基因亞群的分布頻率與先前已發表研究有所差異，例如類費城染色體急性淋巴性白血病在高加索人族群中佔了10-15%，但在台灣族群中卻只有2%。最後我利用多變項分析方法分析，並且確定基因亞群是具有顯著意義的危險因子。藉由本研究的結果，顯示利用轉錄體定序可以檢測B細胞急性淋巴性白血病的基因亞群，且基因亞群的鑑定可以幫助B細胞急性淋巴性白血病的病人進行危險分群。 | zh_TW |
| dc.description.abstract | B-cell acute lymphoblastic leukemia (B-ALL) is the most frequent pediatric malignancy and the outcome had been dramatically improved with risk–directed therapy over the past few decades. The major risk factors include genetic subgroup defined as aneuploidy (high hyperdiploidy or hypodiploidy) or fusion genes and genetic alterations that disrupt B-cell development such as IKZF1 and ERG deletions. Recent years, several large cohort studies had comprehensively analyzed pediatric B-ALL and revealed novel subgroups with distinct gene expression profiles by using RNA-sequencing (RNA-seq) and these subgroups have prognostic significance. To better understand the genomic landscape of pediatric B-ALL in Taiwan, I analyzed recurrent alterations by Multiplex Ligation-dependent Probe Amplification (MLPA), DNA index and RT-PCR. RNA-seq was performed for those cases without known alterations to identify the genetic subgroups. Previous unidentified novel subgroup was discovered by RNA-seq and 90% of cases could be classified as one of the defined genetic subgroups. I also found subgroup-specific alterations that had never been reported such as significant higher rate of IKZF1 deletion and TP53 mutation in DUX4-rearranged ALL and frequent ETV6 alteration in ZNF384-rearranged ALL. The distribution of B-ALL subgroup was different from previous studies such as only 2% of cases were classified as Ph-like in our cohort compared to 10-15% in Caucasian cohorts. Multivariable analysis was performed and subgroup was the significant risk factor. This study showed that RNA-seq can be implemented to discover B-ALL subgroups and identification of genetic subgroup can enhance risk classification of B-ALL. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-20T00:53:42Z (GMT). No. of bitstreams: 1 U0001-2407202015243900.pdf: 12443738 bytes, checksum: de3ea8717a59318fbdb25f36192a4628 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 誌謝 i 摘要 ii Abstract iv Contents vi Abbreviation x List of figures xii List of tables xiv List of appendix tables xv List of appendixes xvi Chapter 1 Introduction 1 1.1 B-cell acute lymphoblastic leukemia 1 1.2 Risk stratification 1 1.3 Genetic subgroups of pediatric B-ALL 3 1.3.1 Aneuploidy 3 1.3.2 Intrachromosomal amplification of chromosome 21 (iAMP21) 5 1.3.3 ETV6–RUNX1 fusion and ETV6–RUNX1-like ALL 5 1.3.4 TCF3-PBX1 fusion ALL 6 1.3.5 KMT2A-rearranged (KMT2A-r) and KMT2A-like ALL 7 1.3.6 BCR-ABL1 fusion and Philadelphia chromosome (Ph)-like ALL 8 1.3.7 DUX4-rearranged (DUX4-r) ALL 10 1.3.8 ZNF384-rearranged (ZNF384-r) and ZNF384-like ALL 11 1.3.9 MEF2D-rearranged (MEF2D-r) ALL 12 1.3.10 PAX5-driven ALL 12 1.3.11 Other subgroups 13 1.4 The specific aims of this study 14 Chapter 2 Material and Methods 16 2.1 Patients and protocols 16 2.2 Purification of lymphocytes from BM or PB specimens 19 2.3 Total RNA extraction 19 2.4 Genomic DNA extraction 20 2.5 Multiplex Ligation-dependent Probe Amplification 21 2.6 Analysis of ploidy status by MLPA 23 2.7 Short tandem repeat (STR) profiling 23 2.8 Chromosomal microarray (CMA) analysis 24 2.9 DNA index (DI) analysis 24 2.10 RT-PCR for fusion genes 25 2.11 PCR for variant analysis 25 2.12 RNA-sequencing 26 2.13 Software 26 2.14 Statistical analysis 27 Chapter 3 Results 29 3.1 DNA index analysis for identification of aneuploidy 29 3.2 MLPA P036 Subtelomeres Mix 1 probemix for identification of aneuploidy 29 3.3 Compare the results between DI, MLPA P036 and karyotyping 30 3.4 High hyperdiploid cases 30 3.5 Hypodiploid cases 31 3.6 Determination of LOH status in hypodiploidy by short tandem repeat (STR) analysis 32 3.7 Identification of iAMP21 by MLPA P327 iAMP21-ERG probemix 32 3.8 RT-PCR for fusion genes 33 3.9 Determine genetic subgroup by RNA sequencing 34 3.10 Copy number abnormalities in children with B-ALL 35 3.11 DUX4-r ALL 35 3.12 MEF2D-r ALL 36 3.13 ZNF384-r ALL 36 3.14 Ph-like ALL 37 3.15 PAX5alt ALL 38 3.16 Other subgroup of B-ALL 39 3.17 Cases with aneuploidy and fusion genes simultaneously 40 3.18 Survival analysis 41 3.19 Multivariate analysis 41 Chapter 4 Discussion 43 4.1 MLPA and DNA index improve the molecular diagnosis of pediatric B-cell acute lymphoblastic leukemia 43 4.2 STR profiling would be a complementary tool for identification of LOH in masked hypodiploidy ALL 44 4.3 Genetic subgroup-specific copy number alterations 44 4.4 The distribution of subgroup of pediatric B-ALL in Taiwan 46 4.5 Pediatric B-ALL cases with multiple primary alterations 48 4.6 Screening strategy for pediatric B-ALL subgrouping in Taiwan 49 4.7 Clinical significance of risk factors 51 Chapter 5 Conclusion and Perspective 52 Figure 55 Table 92 Appendix table 111 Appendix 120 Reference 123 Curriculum Vitae and Publications 136 | |
| dc.language.iso | en | |
| dc.title | 兒童B細胞急性淋巴性白血病之基因分析 | zh_TW |
| dc.title | Genetic Profiling of Pediatric B-cell Acute Lymphoblastic Leukemia | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 楊永立(Yung-Li Yang) | |
| dc.contributor.oralexamcommittee | 俞松良(Sung-Liang Yu),陳璿宇(Hsuan-Yu Chen),邱世欣(Shyh-Shin Chiou),曾慶平(Ching-Ping Tseng) | |
| dc.subject.keyword | 兒童B細胞急性淋巴性白血病,多重連接依賴性探針擴增,DNA指數,轉錄體定序,基因亞群, | zh_TW |
| dc.subject.keyword | Pediatric B-cell acute lymphoblastic leukemia,Multiplex Ligation-dependent Probe Amplification (MLPA),DNA index (DI),RNA-seq,genetic subgroup, | en |
| dc.relation.page | 145 | |
| dc.identifier.doi | 10.6342/NTU202001830 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2020-07-28 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫事技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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