請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74356
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳佑宗 | |
dc.contributor.author | Ying-Hsuan Liaw | en |
dc.contributor.author | 廖盈瑄 | zh_TW |
dc.date.accessioned | 2021-06-17T08:31:28Z | - |
dc.date.available | 2019-08-26 | |
dc.date.copyright | 2019-08-26 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-11 | |
dc.identifier.citation | 1. Jackson, A.L. and L.A. Loeb, The mutation rate and cancer. Genetics, 1998. 148(4): p. 1483-90.
2. Yao, Y. and W. Dai, Genomic Instability and Cancer. J Carcinog Mutagen, 2014. 5. 3. Fu, D., J.A. Calvo, and L.D. Samson, Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer, 2012. 12(2): p. 104-20. 4. Jackson, S.P., Sensing and repairing DNA double-strand breaks. Carcinogenesis, 2002. 23(5): p. 687-96. 5. Li, G.M., Mechanisms and functions of DNA mismatch repair. Cell Res, 2008. 18(1): p. 85-98. 6. Mitchell, J.R., J.H. Hoeijmakers, and L.J. Niedernhofer, Divide and conquer: nucleotide excision repair battles cancer and ageing. Curr Opin Cell Biol, 2003. 15(2): p. 232-40. 7. Wallace, S.S., Base excision repair: a critical player in many games. DNA Repair (Amst), 2014. 19: p. 14-26. 8. Kunkel, T.A., DNA-mismatch repair. The intricacies of eukaryotic spell- checking. Curr Biol, 1995. 5(10): p. 1091-4. 9. Hsieh, P. and K. Yamane, DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev, 2008. 129(7-8): p. 391-407. 10. Li, G.M., DNA mismatch repair and cancer. Front Biosci, 2003. 8: p. d997-1017. 11. McCulloch, S.D., L. Gu, and G.M. Li, Bi-directional processing of DNA loops by mismatch repair-dependent and -independent pathways in human cells. J Biol Chem, 2003. 278(6): p. 3891-6. 12. Liu, D., G. Keijzers, and L.J. Rasmussen, DNA mismatch repair and its many roles in eukaryotic cells. Mutat Res, 2017. 773: p. 174-187. 13. Harfe, B.D. and S. Jinks-Robertson, DNA mismatch repair and genetic instability. Annu Rev Genet, 2000. 34: p. 359-399. 14. Nielsen, F.C., et al., Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with PCNA.Oncogene, 2004. 23(7): p. 1457-68. 15. Longley, M.J., A.J. Pierce, and P. Modrich, DNA polymerase delta is required for human mismatch repair in vitro. J Biol Chem, 1997. 272(16): p. 10917-21. 16. Vilar, E. and S.B. Gruber, Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol, 2010. 7(3): p. 153-62. 17. Boland, C.R., et al., A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of 30 international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res, 1998. 58(22): p. 5248-57. 18. Pritchard, C.C., et al., Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer. Nat Commun, 2014. 5: p.4988. 19. Aaltonen, L.A., et al., Clues to the pathogenesis of familial colorectal cancer. Science, 1993. 260(5109): p. 812-6. 20. Boland, C.R. and A. Goel, Microsatellite instability in colorectal cancer. Gastroenterology, 2010. 138(6): p. 2073-2087 e3. 21. Papadopoulos, N. and A. Lindblom, Molecular basis of HNPCC: mutations of MMR genes. Hum Mutat, 1997. 10(2): p. 89-99. 22. Haraldsdottir, S., et al., Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology, 2014. 147(6): p. 1308-1316 e1. 23. Durno, C.A., et al., Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome. Eur J Cancer, 2015. 51(8): p.977-83. 24. Bruwer, Z., et al., Predictive genetic testing in children: constitutional mismatch repair deficiency cancer predisposing syndrome. J Genet Couns, 2014. 23(2): p.147-55. 25. Subramanian, S., R.K. Mishra, and L. Singh, Genome-wide analysis ofmicrosatellite repeats in humans: their abundance and density in specific genomic regions. Genome Biol, 2003. 4(2): p. R13. 26. Leclercq, S., E. Rivals, and P. Jarne, DNA slippage occurs at microsatellite loci without minimal threshold length in humans: a comparative genomic approach. Genome Biol Evol, 2010. 2: p. 325-35. 27. Duval, A. and R. Hamelin, Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res, 2002. 62(9): p. 2447-54. 28. Myeroff, L.L., et al., A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res, 1995. 55(23): p.5545-7. 29. Wang, J., et al., Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J Biol Chem, 1995. 270(37): p. 22044-9. 30. Souza, R.F., et al., Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Nat Genet, 1996. 14(3): p. 255-7. 31. Malkhosyan, S., et al., Frameshift mutator mutations. Nature, 1996. 382(6591):31 p. 499-500. 32. Rampino, N., et al., Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science, 1997. 275(5302): p.967-9. 33. Woerner, S.M., et al., Pathogenesis of DNA repair-deficient cancers: astatistical meta-analysis of putative Real Common Target genes. Oncogene, 2003. 22(15): p. 2226-35. 34. Wagner, S., C.S. Mullins, and M. Linnebacher, Colorectal cancer vaccines:Tumor-associated antigens vs neoantigens. World J Gastroenterol, 2018. 24(48):p. 5418-5432. 35. Kloor, M. and M. von Knebel Doeberitz, The Immune Biology of Microsatellite-Unstable Cancer. Trends Cancer, 2016. 2(3): p. 121-133. 36. Yamamoto, H. and K. Imai, Microsatellite instability: an update. Arch Toxicol,2015. 89(6): p. 899-921. 37. Tougeron, D., et al., Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations. Mod Pathol, 2009. 22(9): p. 1186-95. 38. Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 2015. 372(26): p. 2509-20. 39. Le, D.T., et al., Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science, 2017. 357(6349): p. 409-413. 40. de la Chapelle, A. and H. Hampel, Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol, 2010. 28(20): p. 3380-7. 41. Vasen, H.F., et al., New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology, 1999. 116(6): p. 1453-6. 42. Bacher, J.W., et al., Improved Detection of Microsatellite Instability in Early Colorectal Lesions. PLoS One, 2015. 10(8): p. e0132727. 43. Muller, A., et al., Challenges and pitfalls in HNPCC screening by microsatellite analysis and immunohistochemistry. J Mol Diagn, 2004. 6(4): p. 308-15. 44. Waalkes, A., et al., Accurate Pan-Cancer Molecular Diagnosis of Microsatellite Instability by Single-Molecule Molecular Inversion Probe Capture and High- Throughput Sequencing. Clin Chem, 2018. 64(6): p. 950-958. 45. Salipante, S.J., et al., Microsatellite instability detection by next generation sequencing. Clin Chem, 2014. 60(9): p. 1192-9. 46. Niu, B., et al., MSIsensor: microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics, 2014. 30(7): p. 1015-6. 47. Hause, R.J., et al., Classification and characterization of microsatellite instability across 18 cancer types. Nat Med, 2016. 22(11): p. 1342-1350. 48. Lee, K., E. Tosti, and W. Edelmann, Mouse models of DNA mismatch repair in cancer research. DNA Repair (Amst), 2016. 38: p. 140-146. 49. Reitmair, A.H., et al., Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice. Cancer Res, 1996. 56(16): p. 3842-9. 50. Edelmann, L. and W. Edelmann, Loss of DNA mismatch repair function and cancer predisposition in the mouse: animal models for human hereditary nonpolyposis colorectal cancer. Am J Med Genet C Semin Med Genet, 2004. 129C(1): p. 91-9. 51. el Marjou, F., et al., Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis, 2004. 39(3): p. 186-93. 52. Toft, N.J., et al., Heterozygosity for p53 promotes microsatellite instability and tumorigenesis on a Msh2 deficient background. Oncogene, 2002. 21(41): p.6299-306. 53. Young, L.C., et al., The associated contributions of p53 and the DNA mismatch repair protein Msh6 to spontaneous tumorigenesis. Carcinogenesis, 2007. 28(10): p. 2131-8. 54. Luo, F., et al., Conditional expression of mutated K-ras accelerates intestinal tumorigenesis in Msh2-deficient mice. Oncogene, 2007. 26(30): p. 4415-27. 55. Wimmer, K. and J. Etzler, Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet, 2008. 124(2): p.105-22. 56. Woerner, S.M., et al., Detection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors. Mol Carcinog, 2015. 54(11): p. 1376-86. 57. Lowsky, R., et al., MSH2-deficient murine lymphomas harbor insertion/deletion mutations in the transforming growth factor beta receptor type 2 gene and display low not high frequency microsatellite instability. Blood, 2000. 95(5): p. 1767-72. 58. Maletzki, C., et al., The mutational profile and infiltration pattern of murine MLH1-/- tumors: concurrences, disparities and cell line establishment for functional analysis. Oncotarget, 2016. 7(33): p. 53583-53598. 59. Fan, H.H., et al., P53 ICE CRIM mouse: a tool to generate mutant allelic series in somatic cells and germ lines for cancer studies. FASEB J, 2019. 33(4): p. 5571-5584. 60. Li, H. and R. Durbin, Fast and accurate short read alignment with Burrows- Wheeler transform. Bioinformatics, 2009. 25(14): p. 1754-60. 61. Wang, K., M. Li, and H. Hakonarson, ANNOVAR: functional annotation of 33 genetic variants from high-throughput sequencing data. Nucleic Acids Res, 2010. 38(16): p. e164. 62. Bacher, J.W., et al., Use of mononucleotide repeat markers for detection of microsatellite instability in mouse tumors. Mol Carcinog, 2005. 44(4): p. 285-92. 63. Woerner, S.M., et al., SelTarbase, a database of human mononucleotide-microsatellite mutations and their potential impact to tumorigenesis and immunology. Nucleic Acids Res, 2010. 38(Database issue): p. D682-9. 64. Maletzki, C., et al., Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome. Mol Carcinog, 2017. 56(7): p. 1753-1764. 65. Bolger, A.M., M. Lohse, and B. Usadel, Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics, 2014. 30(15): p. 2114-20. 66. Quinlan, A.R. and I.M. Hall, BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics, 2010. 26(6): p. 841-2. 67. Koboldt, D.C., et al., VarScan: variant detection in massively parallel sequencing of individual and pooled samples. Bioinformatics, 2009. 25(17): p.2283-5. 68. Cingolani, P., et al., A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin), 2012. 6(2): p. 80-92. 69. Molinari, F. and M. Frattini, Functions and Regulation of the PTEN Gene in Colorectal Cancer. Front Oncol, 2013. 3: p. 326. 70. Markowitz, S., et al., Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science, 1995. 268(5215): p. 1336-8. 71. Jonchere, V., et al., Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite Instability. Cell Mol Gastroenterol Hepatol, 2018. 6(3): p. 277-300. 72. Haigis, K.M., KRAS Alleles: The Devil Is in the Detail. Trends Cancer, 2017.3(10): p. 686-697. 73. Roberts, K.G., et al., Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med, 2014. 371(11): p. 1005-15. 74. Irving, J., et al., Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition. Blood, 2014. 124(23): p. 3420-30. 75. Oliveira, C., et al., Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 34 methylation status. Hum Mol Genet, 2004. 13(19): p. 2303-11. 76. Zhang, J., et al., Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet, 2013. 45(6): p. 602-12. 77. Rajagopalan, H., et al., Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature, 2002. 418(6901): p. 934. 78. Solimini, N.L., et al., STOP gene Phactr4 is a tumor suppressor. Proc Natl Acad Sci U S A, 2013. 110(5): p. E407-14. 79. Kim, T.H., et al., Phactr4 regulates neural tube and optic fissure closure by controlling PP1-, Rb-, and E2F1-regulated cell-cycle progression. Dev Cell, 2007. 13(1): p. 87-102. 80. Bellacosa, A., et al., Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene, 1998. 17(3): p. 313-25. 81. Downward, J., PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol, 2004. 15(2): p. 177-82. 82. Mutter, G.L., et al., Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst, 2000. 92(11): p. 924-30. 83. Peterson, L.M., et al., Molecular characterization of endometrial cancer: a correlative study assessing microsatellite instability, MLH1 hypermethylation, DNA mismatch repair protein expression, and PTEN, PIK3CA, KRAS, and BRAF mutation analysis. Int J Gynecol Pathol, 2012. 31(3): p. 195-205. 84. Karamurzin, Y. and J.K. Rutgers, DNA mismatch repair deficiency in endometrial carcinoma. Int J Gynecol Pathol, 2009. 28(3): p. 239-55. 85. Levine, R.L., et al., PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res, 1998. 58(15): p. 3254-8. 86. Kim, M.S., et al., NIPBL, a cohesion loading factor, is somatically mutated in gastric and colorectal cancers with high microsatellite instability. Dig Dis Sci, 2013. 58(11): p. 3376-8. 87. Wagener, R., et al., The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma. Blood, 2019. 133(9): p. 962-966. 88. Cortes-Ciriano, I., et al., A molecular portrait of microsatellite instability across multiple cancers. Nat Commun, 2017. 8: p. 15180. 89. Bos, J.L., ras oncogenes in human cancer: a review. Cancer Res, 1989. 49(17): p. 4682-9. 90. Barbacid, M., ras genes. Annu Rev Biochem, 1987. 56: p. 779-827. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74356 | - |
dc.description.abstract | DNA錯配修復機制(MMR)在維持基因體穩定性扮演重要的角色,當此機制缺失時會使突變累積進而造成癌症的發生。這些MMR缺失相關癌症被發現有微衛星不穩定(MSI)的特徵,微衛星序列為一至六個核苷酸重複所組成,分布於基因體編碼及非編碼區。這些序列在複製過程時很容易發生錯誤,因此相當依賴MMR機制,然而MMR功能喪失時便會使微衛星序列產生改變。如果分布於編碼區的微衛星序列不穩定時就有可能造成移碼突變,提早產生終止密碼子,進而影響基因的功能。近年來許多研究指出編碼區具有單核苷酸重複序列(cMNR)突變的基因參與在人類MMR缺失癌症進程中,然而在人類較常被報導的cMNR在小鼠內並不一定保守,因此參與MMR缺失癌症的cMNR突變基因在MMR缺失的小鼠模式和人類是否相同仍不完全完全清楚。在這個研究中,我以ICE CRIM系統針對Trp53、Mlh1、Msh2進行破壞,成功建立MMR缺失小鼠模式。另外我設計一個可藉雜交反應來富集相對應基因體序列的探針擷取模組,以次世代定序的方式在我們建立的MMR缺失小鼠模式中偵測MSI靶基因保守性。在我們建立的MMR缺失小鼠模式所產生的MSI-H腫瘤中,我發現無論是保守cMNR區域或是編碼區域的非重複序列皆有出現部分與人類MMR缺失癌症相同的突變基因。另外,我也在一些致癌基因中觀察到出現和人類癌症一樣的突變,例如Kras G12D以及G12V。在小鼠MSI-H腫瘤中出現與人類MSI靶基因保守的小鼠直系同源基因突變顯示使用小鼠研究人類MSI-H腫瘤的可行性。我們研究結果對於參與小鼠MMR缺失癌症的MSI靶基因提供更深入的觀點並有助於我們能更好的了解導致MSI-H腫瘤發生的突變路徑中MMR突變特徵。 | zh_TW |
dc.description.abstract | DNA mismatch repair mechanism (MMR) plays a critical role in maintaining the stability of the genome. Loss of MMR function leads to the accumulation of mutations and promotes tumorigenesis. Microsatellite instability (MSI) is the hallmark of MMR-deficient cancers. Microsatellites are one to six nucleotide repeats, located in either coding or non-coding regions. These repeats are prone to errors and frequently change in size during DNA replication. Normally, the errors are repaired through MMR. In other words, the lengths of microsatellites can be altered when the MMR pathway is defected. If an alteration of the microsatellite length occurred in the coding region, it may cause a frameshift mutation and result in a premature stop codon. Recent studies indicated that some genetic loci carrying coding mononucleotide repeat (cMNR) mutants are involved in the MSI-H carcinogenesis. However, the sequences of these frequently often reported cMNRs in human are not all conserved in mice. So far, whether those cMNR mutations generally seen in human MSI-H tumors are conserved in the MMR-deficient mouse model is unclear. In this study, I disrupted Trp53, Mlh1, and Msh2 by the ICE CRIM system and successfully generated the MMR-deficient mouse model. In addition, I designed a probe capture panel to enrich the conserved MSI target genes in mice for next-generation sequencing analysis. My result identified some conserved MSI target genes in human patient samples and our mouse MSI-H tumors, including both of those mutated in cMNR regions and non-repetitive sequences of coding regions. Oncogenic mutations, identical to those found in human, such as Kras G12D and G12V were observed in our mouse tumorous tissue. The significant enrichment for mouse orthologous variants of the human predicted MSI target genes involved in tumorigenesis reinforce the adequacy of using mice to study human MSI-H tumors. Our study provided an insight into the MSI target genes in MMR-deficient mice and allowed us to better understand the MMR signatures of possible mutational steps leading to MSI-H tumorigenesis. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T08:31:28Z (GMT). No. of bitstreams: 1 ntu-108-R06455001-1.pdf: 9829760 bytes, checksum: fdd2eb84a84b37956ae046806147b8a9 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 口試委員會審定書………………………………………………………………i
致謝………………………………………………………………………………ii 中文摘要……………………………………………………………………………iv Abstract………………………………………………………………………………v Contents……………………………………………………………………………vii List of figures………………………………………………………………………ix List of tables……………………………………………………………………xi List of supplementary tables………………………………………………………xii Supplemental Information…………………………………………………………xiii 1. Introduction………………………………………………………………….…1 1.1 DNA mismatch repair (MMR) mechanism and diseases…….………….…1 1.2 cMNR as a potential target in MSI-H tumors…….………………..……… 3 1.3 Different approaches to detect MSI……………..……...…….…………..…4 1.4 Mouse models to study MMR-associated tumorigenesis…….……….…… 6 1.5 Conserved cMNR genes in human and mouse MSI-H tumors………..……7 2. Materials and methods……………………….……………………………………9 2.1 Animals……………………………………………………………….…. 9 2.2 Genotyping………….…………………………………………………..… 9 2.3 Genomic DNA extraction…………………………………………………10 2.4 Amplicon-based deep sequencing…………………….………………. 10 2.5 Microsatellite analysis……………………….……………………………11 2.6 The DNA capture probe design for MSI target genes panel………………12 2.7 Hybridization-based deep sequencing….…………………………………13 2.8 Sanger Sequencing……………………………………….…………….…15 3. Results……………………………………………………………………….…16 3.1 Generation of MMR-deficient mice by the ICE CRIM system………….16 3.2 Identification of mutations in conserved coding regions of mouse MSI-H tumors……………………………………………………………………18 3.3 Characterization of non-repetitive coding region of disease-related genes in mouse MSI-H tumors…………………………………………………20 4. Discussion……………………………………………………………………….23 5. References………………………………………………………………………30 | |
dc.language.iso | en | |
dc.title | 在小鼠微衛星高度不穩定腫瘤中人類編碼單核苷酸重複序列突變的保守性 | zh_TW |
dc.title | Conservation of human coding mononucleotide repeat mutants in mouse microsatellite instability-high tumors | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 潘思樺,游益興,陳俊銘 | |
dc.subject.keyword | DNA 錯配修復,微衛星不穩定,編碼單核?酸重複序列,MSI 靶基因,小鼠模式, | zh_TW |
dc.subject.keyword | DNA mismatch repair (MMR),microsatellite instability (MSI),coding mononucleotide repeat (cMNR),MSI target genes,mouse model, | en |
dc.relation.page | 75 | |
dc.identifier.doi | 10.6342/NTU201903047 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-08-12 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 基因體暨蛋白體醫學研究所 | zh_TW |
顯示於系所單位: | 基因體暨蛋白體醫學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-108-1.pdf 目前未授權公開取用 | 9.6 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。