“基于表达不平衡的融合基因检测法”在非小细胞肺癌分子分型中的应用

The discovery of fusion genes provide important targets for personalized therapy of non-small-cell lung cancer (NSCLC). The traditional method for detection of fusion genens are consistantly with high price but low efficiency and poor senseitivity. We have obsered the phenomenon of "unbalanced transcription" of fusion genes, that the upstream of the gene is upregulated and the downstream of the gene is downreulated. Based on this finding, we invented the "unbalanced-transcription based fusion gene detection technique", and succeeded in detection of ALK and RET fusion genes in relatively low price, high efficiency and sensitivity. This project go beyond these findings to establish detection priceple and special requirements for the commonly recognized fusion genes. This improvement include the optimiztion in quality control, primer design, thresold setting, and result validation, to construct a systemic analysis of molecular subsets of NSCLC. We will also invetigatie the unknown fusion genens or forms using this technique to find new therapy target by confirming their biological functions. Finally, we would be dedicated to develop cheap, accurate and high through-put fusion gene detection kit, this would be of great help to the molecular diagnosis and genotyping in clinial practice, molecular epidimology investigation and cancer biology analyses.

非小细胞肺癌（NSCLC）中融合基因的发现为个体化治疗提供了重要的靶点，但传统NSCLC融合基因分子诊断技术一直存在价格高、效率低、敏感性较差等缺陷。我们在前期研究中观察到融合基因普遍存在融合点下游高表达、上游低表达的"表达不平衡"的独特现象，基于对"表达不平衡"的检测，初步实现了对ALK、RET两种融合基因低廉、高效、敏感的诊断。本项目拟在此基础上，针对NSCLC公认融合基因种类，设立样本质控、片段设计、诊断阈值和结论验证等环节的一般原则和特殊手段，建立规范化的"基于表达不平衡的融合基因检测法"，进行NSCLC分子分型的整体分析；探索NSCLC中未知的融合基因或融合形式并加分子和功能学验证，提供新的个体化治疗靶点；以期推广成为临床诊断、分子流行病调查、肿瘤生物学研究等领域有效的分子诊断和分子分型手段。

本项目旨在融合基因检测方法创新的基础上，针对NSCLC公认融合基因种类进行研究分析，建立规范化的"基于表达不平衡的融合基因检测法"，进行NSCLC分子分型的整体分析。通过对常见融合基因ALK，ROS1，FGFR等的检测及分析，我们1）成功将"基于表达不平衡的融合基因检测法"运用于临床样本检测；2）发明了一种新的融合基因检测方法；3）证明了FGFR融合基因可作为肺癌靶向治疗的新靶点。本研究针对常见的融合基因做了完整系统性的分析，为临床个体化治疗提供了新靶点，圆满完成预期目标。