近日，國際著名雜志Cell research在線刊登了中科院上海生科院生化與細(xì)胞所季紅斌研究組與復(fù)旦大學(xué)腫瘤醫(yī)院合作的最新研究成果”Identification of RET gene fusion by exon array analyses in "pan-negative" lung adenocarcinomas from never smokers,，”,。文章中，研究者通過對Affymetrix外顯子芯片的分析及實(shí)驗(yàn)驗(yàn)證,，在非吸煙肺腺癌患者中尋找到一個新的致病基因融合CCDC6-RET,。
肺癌是嚴(yán)重危害我國人民生命健康的重大疾病之一,，揭示其中關(guān)鍵的致病基因?qū)榕R床上肺癌的“個體化”分子靶向治療提供潛在的藥靶和新的策略,。季紅斌課題組長期從事肺癌基因組學(xué)的研究，以尋找關(guān)鍵的肺癌致病基因,。該課題組前期的工作為非吸煙肺腺癌患者繪制了較為完備的致病基因圖譜,，揭示了絕大多數(shù)肺腺癌中存在的關(guān)鍵致病基因，而只有少數(shù)肺腺癌（24/202）中的關(guān)鍵致病基因還不得而知,。
目前,，該研究組利用Affymetrix的外顯子芯片，對這些可能具有未知致病基因的肺腺癌樣本進(jìn)行了深入分析,。生物信息學(xué)以及實(shí)驗(yàn)驗(yàn)證結(jié)果表明,，在大約10% (2/24)的腫瘤樣本中存在著一個新的肺癌致病基因融合CCDC6-RET。進(jìn)一步的研究確證了該基因融合來源于染色體DNA水平的轉(zhuǎn)位,。
以往的研究表明該RET基因融合常見于甲狀腺癌樣本中,，它的過表達(dá)會導(dǎo)致腫瘤的發(fā)生,；但關(guān)于該基因融合在其它類型的腫瘤中還未見報道。RET是一個受體酪氨酸激酶,，在正常的肺組織中表達(dá)較低,；而該基因突變?nèi)诤狭薈CDC6的胞外域以及RET的激酶活性區(qū)，在肺癌樣本中往往表達(dá)較高,，而這可能是導(dǎo)致肺癌發(fā)病的關(guān)鍵所在,。
最近在線發(fā)表的三篇Nat Med 文章和一篇Genome Res文章也報道了類似的工作，指出RET融合基因是肺癌中新的關(guān)鍵致病基因,。目前臨床上已經(jīng)有能夠有效抑制RET激酶活性的抑制劑,，因此這些研究對于那些具有RET基因融合的肺腺癌患者的“個體化”治療，將具有直接的指導(dǎo)意義,。
該研究課題獲得科技部,、國家自然科學(xué)基金委和上海市科委的經(jīng)費(fèi)支持。
（生物谷Bioon.com）
doi:10.1038/cr.2012.27
PMC:
PMID:
Identification of RET gene fusion by exon array analyses in "pan-negative" lung adenocarcinomas from never smokers.
Fei Li1,*, Yan Feng1,*, Rong Fang1,*, Zhaoyuan Fang1, Jufeng Xia1, Xiangkun Han1, Xin-Yuan Liu1, Haiquan Chen2,3, Hongyan Liu1 and Hongbin Ji1
The incidence of lung cancer from never smokers has increased dramatically in China nowadays. Strikingly, approximately 30% of the lung cancer patients in East Asian population are never smokers1, 2. The majority of these patients are females with lung adenocarcinomas2. Identification of oncogenic drivers, which the tumors are “addicted to" and rely on for survival, has significantly reformed the current strategies for lung cancer treatment in clinic and initiated the era of personalized therapy3. Therapeutics specifically targeting EGFR mutations, frequently observed in never smoker patients with lung cancer, have been very helpful in improving the clinical symptoms as well as the progression-free survival4, 5, 6. Similarly, patients with lung tumors positive for ALK fusions also benefit from ALK-targeted therapy7, 8. Our previous efforts have constructed a quite comprehensive map of those essential oncogenic drivers in 52 lung adenocarcinomas from never smokers9. We have uncovered the oncognic drivers in about 90% of these lung tumors including mutations of EGFR, HER2, KRAS, as well as EML4-ALK fusion9, thus providing a strong clinical guidance for molecular-targeted therapy for this subset of disease. However, there is still about 10% (5/52) of these never smoker patients were “pan-negative” for all known oncogenic driver mutations and could not benefit from the effective targeted therapy in clinic.
