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研究生:徐意婷
研究生(外文):Hsu, I-Ting
論文名稱:利用血漿DNA微衛星變異為生物標記早期偵測非小細胞肺癌微轉移及發生之評估
論文名稱(外文):The Assessment of Using Microsatellite Alterations in the Plasma DNA as Biomarkers for the Early Detection of Micrometastasis and Occurrence of Non-small Cell Lung Cancer
指導教授:簡一治
指導教授(外文):Chien, Yi-Chih
學位類別:碩士
校院名稱:國立彰化師範大學
系所名稱:生物學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:英文
論文頁數:82
中文關鍵詞:微衛星變異微轉移生物標記非小細胞肺癌
外文關鍵詞:microsatellite alterationmicrometastasisbiomarkernon-small cell lung cancer (NSCLC)
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肺癌可說是目前造成全球癌症死亡率的主要原因之一。肺癌可分為二大類型,而非小細胞肺癌(NSCLC)屬於其中一類。非小細胞肺癌的病患往往因延遲診斷或是癌細胞已有微轉移現象而導致極差的預後情形。微轉移是指病患已有轉移但無法以現有臨床診斷方法偵測的情形。目前臨床上用以偵測微轉移的方法靈敏度均不足,故必須發展出更靈敏且精確的早期診斷轉移的方法。目前正在發展中的方法即是搜尋血漿DNA中微衛星變異的情形,再利用之做為生物標記來偵測微轉移。科學家們已發現癌症病患的血漿DNA具有癌細胞的特徵,如LOH及MSI。且微衛星DNA可以簡易的PCR技術便可容易地偵測到,故微衛星DNA可作為理想的生物標記來用以偵測血漿DNA中LOH及MSI的現象。
我們依據每個微衛星標記的異結合型比例、在腫瘤及血漿DNA中微衛星變異(MA)的情形,將微衛星標記分為四個等級。若某標記異結合型比例≧70%,在腫瘤組織DNA中MA頻率≧50%,且同時在腫瘤及血漿DNA中MA頻率≧30%,則歸類為第一等級。若某標記異結合型比例≧70%,在腫瘤組織DNA中MA頻率也≧50%,但同時在腫瘤及血漿DNA中MA頻率<30%,則屬於第二等級。若某標記異結合型比例≧70%,但在腫瘤組織DNA中MA頻率介於25%-50%,則是第三等級。若某標記異結合型比例≧70%,但在腫瘤組織DNA中MA頻率卻只有<25%,則屬於第四等級,通常被視為最不合適用於微衛星偵測的標記。而第一等級標記則是偵測效果最佳的且最理想的標記。此外,我們尚可由微衛星標記於正常組織DNA中的微衛星變異頻率來判斷在腫瘤發生過程中早期變異的標記。故本研究的目的便在於分析非小型細胞肺癌病患手術前血漿DNA中LOH或MSI情形,篩選出適合的衛星標記,用以早期偵測非小細胞肺癌的發生及微轉移的情形。
我們使用了17組微衛星標記用於檢測26位非小細胞肺癌病患的檢體。發現屬於第一等級的微衛星標記有D3S1300、D8S277及TP53,且最早變異的標記為D18S61。接著,我們又以此四組微衛星標記對控制組做檢測,以釐清其專一性。控制組包含46位非癌症個體及30位非非小細胞肺癌的癌症病患。發現D8S277及D18S61此二組標記在非小細胞患者中的變異頻率與在控制組中無顯著差異。而TP53在非小細胞患者中的變異頻率則是只與在非非小細胞肺癌的癌症病患中無顯著差異。因此D8S277便被排除於第一等級標記之外,而18S61也不被認為適於檢測非小細胞肺癌的早期發生。此外,與臨床特徵作比較後,我們還發現了DS1300的變異似乎與年老者及抽煙者有顯著相關,而TP53則是與較差的癌細胞分化有關。我們計算了FRL指數,發現腫瘤DNA的FRL值是三種DNA中最高的,表示腫瘤DNA具有高度的對偶基因缺失程度,即高度不穩定。
總之,根據我們的研究,D3S1300此微衛星標記被視為是最適合用以偵測非小細胞肺癌且是對非小細胞肺癌最專一的標記。而TP53則是可用以偵測是否患有癌症的通用標記。因此我們建議,若要將微衛星分析應用於臨床上時,可先檢測TP53的變異情形,判斷是否罹患癌症,再以D3S1300進行檢測,來判斷所罹患的癌症是否為非小細胞肺癌。
Lung cancers have been identified to cause one of the major lethality in the world. Non-small cell lung cancer (NSCLC) is one of the two major types of lung cancers. Patients with NSCLC always have very poor prognosis mainly due to late diagnosis, and high rates of micrometastasis, which is the metastatic tumors cannot be detected with current methods in clinic. Current clinical methods of detecting metastasis are not sensitive enough, therefore it’s urgent to develop a more specific and sensitive method. The developing method is to search for microsatellite alterations in plasma DNA in order to use them as biomarkers for detecting micro-metastasis. Scientists have found that the plasma DNA of cancer patients has neoplastic characteristics, such as LOH and MSI. Microsatellite DNA could be detected fast and easily by PCR, which makes it be a good biomarker to detect LOH or MSI in the plasma DNA.
According to the ratio of heterozygosity, microsatellite alterations (MA) in tumor and plasma DNA, microsatellite markers were classified into four grades. Markers with heterozygosity?70%, MA in tumor DNA?50%, and MA in both tumor and plasma DNA?30% were classified as the grade I markers; those with heterozygosity?70%, MA in tumor DNA?50%, and MA in both tumor and plasma DNA<30% were classified as the grade II markers; those with heterozygosity?70% and 25%?MA in tumor DNA<50% were classified as the grade III markers; while those with heterozygosity?70% and MA in tumor DNA<25% were classified as the grade IV, which was considered as unsuitable markers. The grade I markers were regarded as the idealist markers for detection of micro-metastasis. Besides, the markers for the early detection of tumor occurrence could be found by their MA% in the normal tissue DNA. Therefore the aims of this research were to search for grade I microsatellite markers and those had altered in the early stage of the development of NSCLC.
26 NSCLCs were screened with 17 microsatellite markers distributed on 15 chromosome arms. We found that grade I markers were D3S1300, D8S277 and TP53, and the marker altered at the earliest stage of the development of NSCLC was D18S61. These four markers were then tested in control groups, including 46 non-tumor individuals, 30 non-NSCLC patients, to see their specificity to NSCLCs. MA% in the plasma DNA at D8S277 and D18S61 had no significant difference between NSCLC patients and two control groups. And TP53 had no significant difference in MA% in the plasma DNA between patients with NSCLC and non-NSCLC patients. Therefore, D8S277 was further selected out from grade I markers, and D18S61 was considered unsuitable for early detection. Besides, we found MA at D3S1300 associated with older age and smoking, and TP53 related to poor differentiation. FRL index was the highest in the tumor DNA, indicating tumor cells have the highest extent of allelic loss.
In conclusion, D3S1300 was thought to be the most proper and specific marker for NSCLC. However, TP53 was considered as a universal marker for detecting cancers. We suggested TP53 should be examined first to screen if having cancers or not, and then D3S1300 is tested to see if cancers are NSCLCs when practicing in clinic.
Introduction-------------------------------1

Materials and Methods----------------------12

Results------------------------------------16

Discussion---------------------------------22

References---------------------------------39

Appendix-----------------------------------51
Figures----------------------------------51
Tables-----------------------------------66
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