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Transcript
ALK Gene Rearrangement: the Evaluation of a New Strategy for Detecting Fusion Genes 偵測融合基因的新方法評估-以 ALK 為例 Advisor: Dr. Chung-Liang Ho Student: Wan-Li Chen Abstract: Gene fusion is an important somatic mutation in cancers and mainly caused by translocation, inversion and deletion. More than 80% of the known fusion genes were found in rarely happened cancers such as leukemia, lymphoma, bone and soft tissue sarcoma. However, only 10% were discovered in epithelial cancers which account for 80% of cancer-related deaths. Whether such translocation fusion oncogene plays a major role in the pathogenesis of epithelial tumors is still open to question. Nowadays, many treatments targeted to fusion genes which encode proteins with kinase activity and are required for tumorgenesis were validated and applied successfully in the clinical setting. It demonstrated that fusion genes are crucial therapeutic strategies for cancers. Therefore, a high-throughput screening method is needed for differentially detecting fusion genes in solid tumors and discovering possible targets for treatments. RACE (rapid amplification of cDNA ends, RACE) is a common tool for detecting the fusion gene. Due to the low fusion / wild-type transcript ratio, the limitation of this technique is the necessity for large amount of DNA sequencing. Hence, in order to increase the screening throughput, we applied SAGE (serial analysis of gene expression) after RACE. SAGE can give 20 to 30 times more throughput than RACE alone. This novel detection method which combined RACE and SAGE will be designated as SAAT (serial analysis of amplified transcripts). We performed ALK (anaplastic lymphoma kinase) fusion gene analysis to evaluate the feasibility of SAAT. ALK is a receptor tyrosine kinase and first discovered as a product of gene rearrangement in anaplastic large cell lymphoma (ALCL). In 2007, a recurrent chromosome translocation, inv(2)(p21p23), was founded in non–small cell lung cancer (NSCLC). The fusion product is an EML4-ALK fusion-type protein tyrosine kinase. KIF5B-ALK is another fusion-type of ALK in NSCLC discovered in 2009. ALK translocations have been known to recombine with more than 10 different partner genes and still have a number of promisingly fusion partners which had not been found yet. This consequently increases the difficulty on routine molecular diagnosis. Accordingly, in the present study, for the purpose of detecting druggable fusion genes in solid tumors, we established a specific 5’-RACE system for ALK gene and combined with SAGE and further expect to use SAAT to screen large amount samples of NSCLC patients at same time.