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研究生:黃尚本
研究生(外文):Shang-Pen Huang
論文名稱:發現新的生物標記來預測神經膠質瘤病患的預後與治療反應
論文名稱(外文):Identification of New Biomarkers for Predicting Prognosis and Response to therapy in Glioma Patients
指導教授:林源峰林源峰引用關係
口試委員:沈家寧李宏謨趙祖怡梁博煌
口試日期:2017-06-28
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:66
中文關鍵詞:神經膠質瘤生物標記預後抗藥性
外文關鍵詞:GliomaLGGGBMBiomarkerLOXBICD1Temozolomide(TMZ)
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神經膠質瘤(gliomas)根據WHO的定義分為四期,第二、三期神經膠質瘤(grades II and III gliomas)是較低度惡性的神經膠質瘤,又稱lower grade gliomas (LGGs),平均存活時間約為7.5年,但病患的臨床表現與預後差異極大,僅靠目前所使用的病理組織分級(grading)似乎無法精準地預測LGG病人的預後。第四期神經膠質瘤(grade IV glioma)又稱Glioblastomas (GBM)是最惡性的,平均存活時間約14個月,Temozolomide (TMZ)是目前FDA核准唯一有效的化療藥物,但癌細胞對TMZ的抗藥性(drug resistance)是目前臨床醫師最棘手的問題。我們研究的目的是尋找有潛力的分子生物標記(molecular biomarkers),並驗證其臨床價值,期望在臨床運用上能準確地預測LGG病患的預後,及有效地評估GBM病患對TMZ的治療反應。
美國癌症基因圖譜(The Cancer Genome Atlas, TCGA)提供了三組整合性的臨床與基因資料庫,包括TCGA GBM、LGG,以及GBM LGG cohorts。中國神經膠質瘤基因圖譜(Chinese Glioma Genome Atlas, CGGA)也提供了一組資料庫CGGA glioma cohort,藉由上述臨床與基因資料庫分析,我們發現Lysyl oxidase (LOX)的基因表現可能跟LGG病患的預後有關。我們也藉由GBM抗藥細胞株T98G與耐受細胞株U87的基因表現微陣列(Gene expression microarray)分析,發現BICD1的基因表現可能會影響GBM病患對TMZ的治療反應。
我們的結果發現,在LGG病人中,LOX高表現會造成較差的overall survival 與recurrent free survival,LOX高表現的病人在接受primary therapy與follow-up treatment後,治療的結果也較差。在GBM病人中,BICD1高表現會造成較差的overall survival,在接受TMZ或radiation治療的病人中,BICD1高表現也會導致較差的治療反應。我們也發現運用上述的分子生物標記配合病人的其他臨床病理特徵,能更準確的評估病人的預後。最後我們觀察到LOX的表現與IDH1 mutation有顯著相關,且BICD1的表現與epithelial-mesenchymal transition (EMT)也有高度相關,進而提出假說來解釋在神經膠質瘤細胞中,由LOX與BICD1所調控的相關腫瘤存活或抗藥機制。
未來我們會進行一系列的細胞與分生實驗來驗證我們所提出的假說,並期望能將研究結果用於發展個人化醫療(personalized medicine)或精準醫學(precision medicine),以造福更多腦癌病患。
Lower grade gliomas (LGGs) have highly diverse clinical phenotypes. The histological grade and type are insufficient to accurately predict the clinical outcomes of patients with LGG. There is variation in the survival and therapeutic outcome of patients with glioblastomas (GBMs). Therapy resistance is an important challenge in the treatment of GBM patients. Therefore, identifications of biomarkers that can facilitate the prediction of clinical outcomes in LGGs and TMZ resistance in GBMs are urgently needed.
In our study, we analyzed the glioma RNA-seq dataset from TCGA (The Cancer Genome atlas) and identified lysyl oxidase (LOX) as a potential biomarker LGGs. BICD1 expression, related to TMZ-response, was also identified as a candidate biomarker by analysis of the gene-expression profiling in our cell-based microarray. The Kaplan-Meier survival analysis was used to validate the prognostic values of these biomarkers
Our results showed high LOX expression is associated with worse overall survival and recurrence free survival in LGG patients. Moreover, high LOX expression was correlated with the poor outcomes of primary therapy and follow-up treatment in LGG patients. Using the combination of LOX expression with the WHO grade to stratify LGG patients into more distinct subgroups may provide more information for outcome assessment of LGG patients.
Our results also demonstrated that BICD1 expression could predict both the prognosis and response to therapy in GBM patients. High BICD1 expression was correlated with the poor overall survival of GBM patients, and predicted the poor outcome of patients with TMZ or radiation therapies. Besides, using the combination of age, MGMT and BICD1 expression to stratify GBM patients who received TMZ chemotherapy may provide better prediction of the response to TMZ, which may help neuro-oncologists make better individualized therapeutic decisions. Finally, we observed a significant correlation between LOX expression and IDH1 status in LGGs, and a strong relationship between BICD1 expression and the epithelial-mesenchymal transition (EMT) in GBMs, and therefore, proposed possible mechanisms to explain LOX or BICD1-associated survival and therapeutic resistance in gliomas accordingly.
In conclusion, our analyses suggest that LOX expression is a potential biomarker for LGGs, and BICD1 expression is a useful biomarker for prognosis and predicting response to TMZ or radiation therapies in GBM patients. Further investigation is needed to explore the definite mechanism of LOX or BICD1-associated survival or therapeutic resistance in glioma cells by connecting with IDH1-mediated cancer metabolism and the EMT process in cancer progression, which may provide more understanding of glioma pathogenesis and therapeutic resistance, and help neuro-oncologists develop personalized or precision medicine.
Abbreviations………………………………………………………………………….1
中文摘要………………………………………………………………………….….2
Abstract………………………………………………………………………….……3
Introduction……………………………………………………………………………5
1.1 Backgrounds of lower grade gliomas (LGGs)…..……………….…………5
1.2 Backgrounds of glioblastoma multiforme (GBMs)…….…………………5
Materials and Methods………………………………………………………………7
Results…………………………………………………...……………………….…..10
Part I. LOX expression in LGGs……………………………….…………...…10
2.1.1 Identification of potential biomarkers.……....……………………10
2.1.2 Validating the prognostic values of biomarker candidates…………11
2.1.3 The underlying mechanism………………………………………13
2.1.4 Clinical application………………….……………………………14
Part II. BICD1 expression in GBMs………………………………………….…15
2.2.1 Identification of potential biomarkers……………………………15
2.2.2 Validating the prognostic values of biomarker candidates…………16
2.2.3 The underlying mechanism……………………….………………19
2.2.4 Clinical application………………………………………………19
Discussion……………………………………………………………………………23
3.1 LOX expression as a biomarker of LGGs……..………………………..…23
3.2 BICD1 expression as a biomarker of GBMs………………………………25
Reference………………………………………………………………………….…28
Tables………………………………………………………………………………32
Figures and legends………...………………………………………………...………35
Appendix…………………………………………………………………….……….61
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