Myxofibrosarcoma 其特點是廣泛的組織變異，從看似較良性型態至出現大量歧異腫瘤細胞之多形性肉瘤。該腫瘤之基因背景為高度變異的基因體，因此在闡明分子畸變在惡性腫瘤的進展中唯一相當合適的模型。我們研究團隊使用全基因組陣列比較基因組雜交，​​在myxofibrosarcoma樣本和細胞株中發現許多不正常的DNA套數，在綜合基因表現子分析後，我們發現在5號染色體短臂上SKP2的基因增幅、9號染色體短臂上MTAP的同合子基因缺失，以及一可能之腫瘤抑制基因ASS1的表現缺失。並推測該些缺失可能與肉瘤生成相關。

SKP2的基因增幅顯然是基因過度表現的主要的驅動機制，其可在三分之一的腫瘤中發現，並
SKP2免疫組化染色強度相關。此外，其基因放大也暗示了較短的病人的存活。除了傳統已知SKP2
促進細胞增殖和腫瘤生長相關外，我們也證實了SKP2與腫瘤轉移相關，其可能藉由調控ITGB2，ACTN1，IGF1，及ENAH促進細胞轉移。

有趣的是MTAP和ASS1分別是細胞核質生成和氨基酸的合成途徑中的關鍵蛋白質，其表現缺失暗示著代謝恆定的變異是在肉瘤生成中很重要的機轉。在我們的研究中，我們不僅證明了他們的缺失和/或表觀基因靜默在myxofibrosaroma 中確實存在，我們亦分別評估L-alanosine以及ADI-PEG20在MTAP或ASS1 表現缺失細胞及其動物模型治療的成效，同時也證實了該二基因為新穎腫瘤抑制基因，並特別在抑制腫瘤血管生成上有顯著影響。

我們的研究提供了進一步了解腫瘤進展的分子致病機制，生物學意義和潛在的治療相關意涵。

Characterized by a wide histological spectrum, myxofibrosarcoma ranges from deceptively bland-appearing lesions to frankly pleomorphic sarcomas, representing a suitable model to elucidate the molecular aberrations in multistep disease progression. Using genome-wide array comparative genomic hybridization, we have profiled DNA copy number alterations in myxofibrosarcoma samples and cell lines in coupled with expression profiling data and identified prominent SKP2 amplification on 5p, frequent homozygous deletion of MTAP on 9p, as well as loss expression of ASS1, a candidate tumor suppressor.
As a predominant driving mechanism, SKP2 gene amplification was detected in one-third of cases in independent cohort validation and associated with SKP2 immunohistochemical expression, adverse prognosticators, and worse patient survival. Besides the classical attribute in promoting cell proliferation and tumor growth, we have confirmed the pro-metastatic oncogenic function of SKP2 and identified differentially expressed motility-promoting genes as its potential mediators, including ITGB2, ACTN1, IGF1, and ENAH.
Since MTAP and ASS1 are key enzymes in either salvage pathway of nucleologenesis and amino acid biosynthesis, their deficiency suggests alterations involving metabolic homeostasis is important in sarcomagenesis. We in our studies not only validated their deletion and/or epigenetic silencing in myxofibrosaroma, evaluating the therapeutic responses of L-alanosine and ADI-PEG20 in MTAP or ASS1 deficient cells in vitro and in vivo, but also confirmed their tumor suppressor functions with special focus on tumor angiogenesis.
Our study provides further insight into the molecular pathogenesis in tumor progression and highlights the prognostic, biological, and potential therapeutic relevance in myxofibrosarcoma.

Table of Content

Acknowledge i
Content ii
Chinese Abstract iii
English Abstract iv
Table of Content v
Chapter-I Targeting gene deletion in sarcoma 1-34
Chapter-II Targeting gene amplification in sarcoma 35-96
Chapter-III Targeting epigenetic alteration in sarcoma 97-163
Chapter-IV Other publications 164-172
Perspective 173-175

Section-I
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48. Marce S, Balague O, Colomo L, et al. Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: implications for a potential targeted therapy. Clin Cancer Res 2006;12: 3754-61.
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Section-II
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3. Lin CN, Chou SC, Li CF, Tsai KB, Chen WC. Hsiung CY, et al. Prognostic factors of myxofibrosarcomas: implications of margin status, tumor necrosis, and mitotic rate on survival. J Surg Oncol 2006;93:294-303.
4. Oda Y, Takahira T, Kawaguchi K, Yamamoto H, Tamiya S, Matsuda S,
et al. Altered expression of cell cycle regulators in myxofibrosarcoma, with special emphasis on their prognostic implications. Hum Pathol 2003;34:1035-42.
5. Sanfilippo R, Miceli R, Grosso F, Fiore M, Puma E, Pennacchioli E, et al. Myxofibrosarcoma: prognostic factors and survival in a series of patients treated at a single institution. Annals of surgical oncology 2011;18:720-5.
6. Barretina J, Taylor BS, Banerji S, Ramos AH, Lagos-Quintana M, Decarolis PL, et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet 2010;42:715-21.
7. Willems SM, Debiec-Rychter M, Szuhai K, Hogendoorn PC, Sciot R. Local recurrence of myxofibrosarcoma is associated with increase in tumour grade and cytogenetic aberrations, suggesting a multistep tumour progression model. Mod Pathol 2006;19(3):407-16.
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9. Huang HY, Kang HY, Li CF, Eng HL, Chou SC, Lin CN, et al. Skp2 overexpression is highly representative of intrinsic biological aggressiveness and independently associated with poor prognosis in primary localized myxofibrosarcomas. Clin Cancer Res 2006;12:487-98.
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11. Krause AK, Hinrichs SH, Orndal C, DeBoer J, Neff JR, Bridge JA. Characterization of a human myxoid malignant fibrous histiocytoma cell line, OH931. Cancer Genet Cytogenet 1997;94:138-43.
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Section-III
1. Lin CN, Chou SC, Li CF, Tsai KB, Chen WC, Hsiung CY, et al. Prognostic factors of myxofibrosarcomas: implications of margin status, tumor necrosis, and mitotic rate on survival. J Surg Oncol 2006;93:294-303.
2. Mentzel T, Calonje E, Wadden C, Camplejohn RS, Beham A, Smith MA, et al. Myxofibrosarcoma. Clinicopathologic analysis of 75 cases with emphasis on the low-grade variant. Am J Surg Pathol 1996;20:391-405.
3. Mutter RW, Singer S, Zhang Z, Brennan MF, Alektiar KM. The enigma of myxofibrosarcoma of the extremity. Cancer 2012;118:518-27.
4. Li CF, Wang JM, Kang HY, Huang CK, Wang JW, Fang FM, et al. Characterization of gene amplification-driven SKP2 overexpression in myxofibrosarcoma: potential implications in tumor progression and therapeutics. Clin Cancer Res 2012;18:1598-610.
5. Willems SM, Debiec-Rychter M, Szuhai K, Hogendoorn PC, Sciot R. Local recurrence of myxofibrosarcoma is associated with increase in tumour grade and cytogenetic aberrations, suggesting a multistep tumour progression model. Mod Pathol 2006;19:407-16.
6. Oda Y, Takahira T, Kawaguchi K, Yamamoto H, Tamiya S, Matsuda S, et al. Altered expression of cell cycle regulators in myxofibrosarcoma, with special emphasis on their prognostic implications. Hum Pathol 2003;34:1035-42.
7. Sanfilippo R, Miceli R, Grosso F, Fiore M, Puma E, Pennacchioli E, et al. Myxofibrosarcoma: prognostic factors and survival in a series of patients treated at a single institution. Annals of surgical oncology 2011;18:720-5.
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13. Barretina J, Taylor BS, Banerji S, Ramos AH, Lagos-Quintana M, Decarolis PL, et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet 2010;42:715-21.
14. Snijders AM, Nowak N, Segraves R, Blackwood S, Brown N,Conroy J, et al. Assembly of microarrays for genome-wide measurement of DNA copy number. Nat Genet 2001;29:263-4.
15. Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 2010;10:267-77.
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19. Wheatley DN. Arginine deprivation and metabolomics: important aspects of intermediary metabolism in relation to the differential sensitivity of normal and tumour cells. Semin Cancer Biol 2005;15:247-53.
20. Delage B, Fennell DA, Nicholson L, McNeish I, Lemoine NR, Crook T, et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer 2010;126:2762-72.
21. Yang TS, Lu SN, Chao Y, Sheen IS., Lin CC, Wang TE, et al. A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br J Cancer 2010;103:954-60.
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