2010-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647988摘要：在癌細胞中，體細胞基因的突變或基因表現改變是常見的現象。特殊的突變有時在癌症的診斷中扮演重要角色。抑制這些特殊突變或訊息路徑是癌症標靶治療常用方針。以表皮生長因子受體(EGFR)之於非小細胞肺癌為例，酪胺酸激酶抑制劑對特殊EGFR突變的非小細胞肺癌有高度療效，但對沒有突變的肺癌則效果不佳。其他基因突變也可在非小細胞肺癌發現，例如：K-Ras、HER2、B-Raf、PIK3CA、EML4-ALK、LKB1 或TP53。對於多數非小細胞肺癌而言，診斷時所採集到的切片檢體在初步病理化驗後往往只剩少量檢體供分子檢驗，對於需接受全身性治療的非小細胞肺癌，能接受完整EGFR 突變分析的病患不到40%。目前已有技術利用微量檢體，例如：細針抽取物、循環癌細胞或血清DNA，來放大微量DNA，但這些技術的敏感性與特異性尚未確認。由於EGFR 或其他基因突變會影響病患的治療決策，發展準確的技術來偵測這些突變相當重要。本研究計畫採集有這些特殊突變癌細胞異種皮移植的動物血液來鑑定這些DNA 放大技術的可行性。我們也將收集非小細胞肺癌病患的抽取物或體液，萃取其DNA 偵測其中基因突變。我們將利用各種技術中最準確的一種來分析特殊突變在腫瘤組織及血清中的相關性，也會分析各種突變與病患接受的治療內容、治療結果與病患存活的相關性。<br> Abstract: Somatic gene mutation or expression level alterations are frequently found in cancer cells.Specific mutations are sometimes diagnostic for certain types of cancer. The presence ofthese specific mutations sometimes link to the carcinogenesis or tumor progression process.Thus, inhibiting the specific mutation related pathway is a commonly used strategy todevelop targeted therapies. The specific mutations of epidermal growth factor receptor(EGFR) in nonsmoking nonsmall cell lung cancer (NSCLC) patients is a good example.Tyrosine kinase inhibitors (TKI) of EGFR are highly effective for the treatment of NSCLCpatients with specific EGFR mutations. EGFR-TKIs are not effective at all in NSCLCpatients with similar clinical characteristics but without EGFR mutation. Thus, detection ofspecific EGFR mutations in NSCLC patients is important for selection of targeted therapyover chemotherapy. Unfortunately, for most of NSCLC patients, diagnosis are oftenaccomplished by small biopsy samples. Few materials are left after initial pathologicaldiagnosis for further molecular diagnosis. EGFR mutation tests can only be completed inless than 40% of patients who are eligible for treatment with systemic chemotherapy. It isimportant to develop methodology to detect specific mutation with minute amount ofsamples, such as cells from fine-needle aspirates, circulating cancer cells or plasma DNA.Several DNA amplification strategies are available at present. EGFR mutations can bedetected in DNA samples from circulating cancer cells, fine needle aspirates or plasma DNAin a few preliminary reports. However, the specificity and sensitivity as well as thecorrelation of test result to treatment result are not available. Since EGFR mutation isfrequently detected in our NSCLC patient population, it is important that we develop validnon-invasive specific mutation detection method. The test results may guild our treatmentoptions and future research. Other specific mutations can be found in less than 10% ofNSCLC. For examples, k-ras, HER2, b-raf, PIK3CA, EML4-ALK fusion protein, LKB1, orp53 are found in small percentage of tumor samples. In some patients with these raremutations, their cancer was successfully treated with specific inhibitors. Therefore,developing methods that detect these rare mutations in small amount of DNA sample isimportant.We plan use blood collected from xenograft models of NSCLC cells bearing thespecific mutations to test the feasibility of DNA amplification technologies.We will collectblood samples and tumor aspirates as well as other tissue fluid from advanced stage NSCLCpatients. DNA will be extracted and specific mutations of EGFR, K-ras, etc. will be detectedby various amplification technologies. Most sensitive method will be selected for futurestudies. Specific mutations in tumor sample and plasma samples will be correlated. Thetreatment outcome and survival of participated subjects with available treatment informationwill be analyzed.