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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 楊偉勛 | |
| dc.contributor.author | Yuh-Tsyr Chou | en |
| dc.contributor.author | 周毓慈 | zh_TW |
| dc.date.accessioned | 2021-06-17T08:06:28Z | - |
| dc.date.available | 2022-01-01 | |
| dc.date.copyright | 2019-08-27 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-08-19 | |
| dc.identifier.citation | 1. Kantorovich, V. and Pacak K., Pheochromocytoma and Paraganglioma, in Neuroendocrinology - Pathological Situations and Diseases. 2010. p. 343-373.
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N Engl J Med, 2007. 356(6): p. 601-10. 16. Kopetschke, R., et al., Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma. Eur J Endocrinol, 2009. 161(2): p. 355-61. 17. Klein R., Lloyd R., and Young W. Hereditary Paraganglioma-Pheochromocytoma Syndromes. 2018 Oct 4 2008 May 21]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK1548/. 18. Lenders, J.W., et al., Biochemical diagnosis of pheochromocytoma: which test is best? JAMA, 2002. 287(11): p. 1427-34. 19. Sawka, A.M., et al., A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab, 2003. 88(2): p. 553-8. 20. Perry, C.G., et al., The diagnostic efficacy of urinary fractionated metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma. Clin Endocrinol (Oxf), 2007. 66(5): p. 703-8. 21. Ilias, I. and K. Pacak, Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab, 2004. 89(2): p. 479-91. 22. N, F., et al., Diagnosis of pheochromocytoma using [123I]-compared with [131I]-metaiodobenzylguanidine scintigraphy. Int J Urol, 1999. 6(3): p. 119-124. 23. Plouin, P.F., et al., Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension, 1997. 29(5): p. 1133-1139. 24. Group, N.G.S.i.P.S., et al., Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol, 2017. 13(4): p. 233-247. 25. Li H. and Durbin R., Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 2009. 25(14): p. 1754-60. 26. McKenna, A., et al., The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res, 2010. 20(9): p. 1297-303. 27. DePristo, M.A., et al., A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet, 2011. 43(5): p. 491-8. 28. Wang, K., M. Li, and H. Hakonarson, ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res, 2010. 38(16): p. e164. 29. San Lucas, F.A., et al., Integrated annotation and analysis of genetic variants from next-generation sequencing studies with variant tools. Bioinformatics, 2012. 28(3): p. 421-2. 30. Kumar, P., S. Henikoff, and P.C. Ng, Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc, 2009. 4(7): p. 1073-81. 31. Adzhubei, I.A., et al., A method and server for predicting damaging missense mutations. Nat Methods, 2010. 7(4): p. 248-9. 32. Robinson, J.T., et al., Integrative genomics viewer. Nat Biotechnol, 2011. 29(1): p. 24-6. 33. Thorvaldsdottir, H., J.T. Robinson, and J.P. Mesirov, Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform, 2013. 14(2): p. 178-92. 34. Muth, A., et al., Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma. J Intern Med, 2019. 285(2): p. 187-204. 35. Huang, Y., et al., Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients. Endocr Connect, 2018. 7(12): p. 1217-1225. 36. Hong, A., et al., Higher risk of phaeochromocytoma/paraganglioma (Phaeo-Pgl) in SDHD than SDHB carriers: an Australian cohort study. Intern Med J, 2019. 49(4): p. 529-532. 37. Donato, S., et al., SDHx-related pheochromocytoma/paraganglioma - genetic, clinical, and treatment outcomes in a series of 30 patients from a single center. Endocrine, 2019. 38. Fishbein, L., Pheochromocytoma and Paraganglioma: Genetics, Diagnosis, and Treatment. Hematol Oncol Clin North Am, 2016. 30(1): p. 135-50. 39. Wong, M.Y., et al., Clinical Practice Guidance: Surveillance for phaeochromocytoma and paraganglioma in paediatric succinate dehydrogenase gene mutation carriers. Clin Endocrinol (Oxf), 2019. 90(4): p. 499-505. 40. Badenhop, R.F., et al., Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. Genes Chromosomes Cancer, 2001. 31(3): p. 255-63. 41. Lee, S.C., et al., Hereditary paraganglioma due to the SDHD M1I mutation in a second Chinese family: a founder effect? Laryngoscope, 2003. 113(6): p. 1055-8. 42. Dreijerink, K.M.A., et al., Biochemically silent sympathetic Paraganglioma, Pheochromocytoma or Metastatic Disease in SDHD mutation carriers. J Clin Endocrinol Metab, 2019. 43. Yao, L., et al., Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA, 2010. 304(23): p. 2611-9. 44. K., I., et al., A variety of phenotype with R161Q germline mutation of the von Hippel-Lindau tumor suppressor gene in Japanese kindred. Int J Med., 2004. 13(3): p. 401-404. 45. Santarpia, L., D. Lapa, and S. Benvenga, Germline mutation of von Hippel-Lindau (VHL) gene 695 G>A (R161Q) in a patient with a peculiar phenotype with type 2C VHL syndrome. Ann N Y Acad Sci, 2006. 1073: p. 198-202. 46. Qi, X.P., et al., p.N78S and p.R161Q germline mutations of the VHL gene are present in von Hippel-Lindau syndrome in two pedigrees. Mol Med Rep, 2013. 8(3): p. 799-805. 47. Curras-Freixes, M., et al., Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. J Med Genet, 2015. 52(10): p. 647-56. 48. Castellone, M.D., et al., A novel de novo germ-line V292M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterization. Clin Endocrinol (Oxf), 2010. 73(4): p. 529-34. 49. Qi, X.P., et al., RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family. PLoS One, 2011. 6(5): p. e20353. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73591 | - |
| dc.description.abstract | 嗜鉻細胞瘤(pheochromocytoma, PCC)和副神經節瘤(paraganglioma, PGL)為神經內分泌腫瘤的一種，分別長在腎上腺或是腎上腺外的嗜鉻細胞中。這樣的腫瘤大部分是良性的，但由於過度增生的嗜鉻細胞會不斷分泌兒茶酚胺(catecholamine)，而兒茶酚胺會使心跳加速、心臟收縮力增強、血壓上升等，長期兒茶酚胺過高會導致高血壓、心律不整、中風而增加患者的死亡率。約有三分之一的嗜鉻細胞瘤/副神經節瘤患者帶有遺傳性的致病基因變異，所以本研究的目的為建立一個次世代定序(next-generation sequencing, NGS)的基因檢測平台，幫助這些患者找出致病基因變異位點。
根據前人的研究，我們設計了一個32個基因群的檢測平台，包含12個最常見的致病基因(RET, VHL, NF1,FH, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127, EGLN1(PHD2))、10個體細胞變異基因(ARNT(HIF1β), ATRX, BRAF, CSDE1, EPAS1(HIF1α), FGFR1, HRAS, IDH1, SETD2, TP53)、3個融合基因 (BRAF, MAML3, NGFR)及其它7個曾被報導過的致病基因(CDKN2A , H3F3A, IDH2, KMT2D, MDH2C, MERTK, MET)。我們利用Illumina MiSeq平台產出雙端定序(paired-end)序列，經由軟體分析產出變異位點，比對資料庫(gnomAD, ExAC, Taiwan Biobank)的等位基因频率篩選可能的點位，最後藉由2015年ACMG的準則判斷變異位點的致病性。 本研究結果顯示，我們在41個家族中找到12個家族帶有遺傳性的致病變異位點，檢出率約為29%，與前人研究的33%相近。這12個家族帶的遺傳性致病變異位點由7個不同的變異位點組成，其中有7個家族帶有相同的致病變異位點(SDHD, c.3G>C, p.M1X, NM_003002)，暗示這個能是一個創立者效應(founder effect)，但還需要一後續的實驗來驗證這個說法。帶有SDHB及SDHD致病變異位點的患者在收案的3年內都看到了轉移現象，與過去文獻中轉移機率最高的基因SDHB稍有不同。另外，在TMEM127及RET基因上的變異位點，因其族群基因頻率低、軟體預測為可能影響蛋白質功能及缺乏完整研究，故值得做相關功能性試驗以釐清其致病性。 | zh_TW |
| dc.description.abstract | Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumors arising from adrenal and extra-adrenal chromaffin cells respectively. They mostly present benign, yet show high morbidity and mortality due to the overproduction of catecholamine, which leads to hypertension, arrhythmia and even ischemia stroke. About one thirds of PCC/PGL are caused by germline genetic variants; therefore, here we established a NGS panel to detect possible disease-causing variants. After literature review, we aimed at the top 12 PCC/PGL causative genes (RET, VHL, NF1,FH, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127, EGLN1(PHD2)), 10 somatic mutation genes (ARNT(HIF1β), ATRX, BRAF, CSDE1, EPAS1(HIF1α), FGFR1, HRAS, IDH1, SETD2, TP53), 3 fusion genes (BRAF, MAML3, NGFR) and other 7 genes (CDKN2A , H3F3A, IDH2, KMT2D, MDH2C, MERTK, MET) which were reported relative to PCC/PGL. Paired-end reads were generated from Illumina MiSeq platform and analyzed with in-house pipeline (BWA-MEM, Picard SortSam, MarkDuplicates, GATK-BQSR and ANNOVAR). Variants were filtering according to the allele frequencies in gnomAD, ExAC and Taiwan Biobank, and the pathogenicity interpretation were facilitated by disease/gene database, scientific literature and the 2015 ACMG Guidelines. In this study, we sequenced 41 probands and yielded approximately 29% diagnosis rate with identifying 7 different disease-causing variants and several variants of unknown significant (VUS). Among the results, seven unrelated probands carried a same causative variant in SDHD (c.3G>C, p.M1X, NM_003002), which implied a founder mutation in Taiwan. Three different variants of SDHB and SDHD in nine unrelated probands showed metastasis in our study. Variants in TMEM127 and RET showed low allele frequency or absent in population database and predicted to affect protein function deserved further functional study. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T08:06:28Z (GMT). No. of bitstreams: 1 ntu-108-P06448007-1.pdf: 3547686 bytes, checksum: de1471dac5cfd3e3ff23434ccd05e699 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
序言 ii Abstract iii 中文摘要 v Table of Contents vii List of Figures x List of Table xi Chapter 1: Research Background and Motivation 1 1-1 Disease introduction 1 1-2 History of heredity PPGL 1 1-3 Prevalence and inheritance pattern 2 1-5 Diagnosis and management 5 1-6 Motivation and purpose 6 Chapter 2: Research Methodology 8 2-1 Experimental design 8 2-2 Sample and clinical data 8 2-3 DNA extraction 9 2-4 DNA quality check 10 2-5 PPGL NGS panel design 11 2-6 Sample preparation and massively parallel sequencing 13 2-7 Data analysis 13 Chapter 3: Results 17 3-1 Results overview 17 3-2 Supporting evidence for the pathogenic variants and Sanger confirmation 18 3-2-1 MAX exon3:c.157delC, p.Q53fs 18 3-2-2 SDHB exon2:c.136C>T, p.R46X 19 3-2-3 SDHB exon3:c.268C>T, p.R90X 19 3-2-4 SDHD exon1:c.3G>C, p.0 20 3-2-5 TMEM127 exon4:c.499_500insGAT, p.S167delinsX 20 Chapter 4: Discussion 30 4-1 Diagnosis rate compared with previous research 30 4-2 SDHD c.3G>C variant may be a founder mutation 30 4-3 TMEM127 variant will not cause NMD but still affect protein function 31 4-4 PF040 –VHL, p.R161Q and RET, p.V292M 31 4-5 Future work 32 Chapter 5: Conclusion 34 Chapter 6: Reference 35 | |
| dc.language.iso | en | |
| dc.title | 以次世代定序鑑定台灣地區嗜鉻細胞瘤及副神經節瘤之致病變異位點 | zh_TW |
| dc.title | Identifying Causative Genetic Variants of Pheochromocytoma and Paraganglioma by Next-Generation Sequencing (NGS) in Taiwan | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 陳沛隆 | |
| dc.contributor.oralexamcommittee | 曾芬郁 | |
| dc.subject.keyword | 嗜鉻細胞瘤,副神經節瘤,基因檢測,世代定序, | zh_TW |
| dc.subject.keyword | pheochromocytoma,paraganglioma,genetic testing,next-generation sequencing (NGS), | en |
| dc.relation.page | 41 | |
| dc.identifier.doi | 10.6342/NTU201904043 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-08-19 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| Appears in Collections: | 分子醫學研究所 | |
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| ntu-108-1.pdf Restricted Access | 3.46 MB | Adobe PDF |
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