在我國(guó)，每年約有40萬(wàn)人死于肺癌,，在各類(lèi)癌癥引起的死亡中高居榜首,。肺腺癌是肺癌的各種亞類(lèi)中最常見(jiàn)的類(lèi)型，在每年全球確診的新增肺癌病患中約占40%,。研究肺癌中基因突變對(duì)肺癌的臨床診斷和預(yù)后有著重要的意義,。近日，國(guó)際肺癌研究協(xié)會(huì)舉辦的專(zhuān)業(yè)學(xué)術(shù)期刊Journal of Thoracic Oncology在線(xiàn)發(fā)表了生化與細(xì)胞所季紅斌研究組與復(fù)旦大學(xué)腫瘤醫(yī)院合作開(kāi)展的最新研究成果,，報(bào)道了中國(guó)肺腺癌人群中熱點(diǎn)基因LKB1,、EGFR和KRAS的突變譜。
LKB1又名STK11 (serine threonine kinase 11),，是絲氨酸蘇氨酸激酶家族的成員,，并且是家族性黑斑息肉綜合癥的致病基因。季紅斌研究組此前的工作發(fā)現(xiàn)抑癌基因LKB1對(duì)腫瘤的轉(zhuǎn)移有著重要的影響,，其蛋白缺失可顯著提高腫瘤細(xì)胞的轉(zhuǎn)移,。表皮生長(zhǎng)因子EGFR是介導(dǎo)細(xì)胞生長(zhǎng)信號(hào)的重要分子，并且在臨床上攜帶該基因突的肺癌患者對(duì)抑制酪氨酸激酶的小分子化合物抑制劑（Tyrosine Kinase inhibitors,，TKIs）有著很高的響應(yīng),。KRAS是EGFR通路下游的重要信號(hào)分子，對(duì)MAPK通路有著直接的調(diào)節(jié)作用,。上述三個(gè)基因在西方肺癌人群中有著相當(dāng)比例的突變率,，在亞洲包括韓國(guó)和日本肺癌人群中也有一定研究。我國(guó)的肺癌人群中LKB1,，EGFR和KRAS突變的總體特征尚缺乏較為全面的認(rèn)識(shí),。
生化與細(xì)胞所季紅斌課題組聯(lián)合復(fù)旦大學(xué)腫瘤醫(yī)院陳海泉主任領(lǐng)導(dǎo)的胸外科研究室對(duì)中國(guó)肺腺癌人群中重要的基因突變進(jìn)行了篩查。他們篩查的結(jié)果發(fā)現(xiàn)LKB1在中國(guó)肺腺癌人群中的突變率為6.9%,，而且LKB1突變主要來(lái)自吸煙患者,。LKB1的F354L變異在肺腺癌人群中的比例約為10.5%且均為種系遺傳（即從父母遺傳而來(lái)），其中兩例患者的腫瘤組織內(nèi)F354L變異發(fā)生了雜合性缺失,，提示該位點(diǎn)在肺癌的發(fā)生或發(fā)展中可能有著尚待探明的作用,。與此同時(shí)，在中國(guó)肺腺癌人群中發(fā)現(xiàn)的EGFR突變率為66.3%,，KRAS突變僅為2.3%,。在EGFR突變中，較為引人注意的是女性非吸煙患者的突變率高達(dá)83.8%,，提示該類(lèi)肺腺癌人群具有高度的EGFR突變傾向,，并且可能作為T(mén)KIs小分子藥物治療的重點(diǎn)人群。這些工作為全面而深入地揭示中國(guó)肺癌人群的基因突變譜奠定了一個(gè)良好的基礎(chǔ),。
該項(xiàng)工作得到了國(guó)家科技部,、國(guó)家自然科學(xué)基金委,、中科院及上海市科委的經(jīng)費(fèi)支持。(生物谷www.Bioon.net)
生物谷推薦原文出處：
J Thorac Oncol. 2010 Jun 16;:20559149
Spectrum of LKB1, EGFR, and KRAS Mutations in Chinese Lung Adenocarcinomas.
Bin Gao, Yihua Sun, Junhua Zhang, Yan Ren, Rong Fang, Xiangkun Han, Lei Shen, Xin-Yuan Liu, William Pao, Haiquan Chen, Hongbin Ji
*Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; Departments of daggerThoracic Surgery and double daggerPathology, Shanghai Cancer Hospital, Fudan University, Shanghai, China; and section signVanderbilt-Ingram Cancer Center, Nashville, Tennessee.
INTRODUCTION:: Somatic LKB1 mutations are found in lung adenocarcinomas at different frequencies in Caucasian and East Asian (Japanese and Korean) populations. This study was designed to characterize the frequency of LKB1 mutations, their relationship to EGFR and KRAS mutations, and their associated clinicopathologic characteristics in Chinese patients. METHODS:: Two hundred thirty-nine lung adenocarcinomas consecutively collected from October 2007 to July 2009 were dissected into 3 to 4 small (3 mm) pieces for histopathological analyses of tumor content. Genomic DNA and/or cDNA from 86 samples with more than 70% tumor content were used for sequencing of LKB1 (exons 1-9), EGFR (exons 18-21), and KRAS (exon 2). LKB1 germline mutation status was determined by sequencing of genomic DNA from matched histologically distant lung tissues that are histologically normal. RESULTS:: 6.9% of lung adenocarcinomas harbored LKB1 somatic mutations. A total of 10.5% of patients had an LKB1 germline polymorphism, F354L. Interestingly, in two of these patients, tumors displayed loss of heterozygosity at this allele. EGFR kinase domain and KRAS mutations were found in 66.3% and 2.3% of Chinese lung adenocarcinomas, respectively. Concurrent LKB1 and EGFR somatic mutations were observed in one patient. Both KRAS-mutant tumors harbored LKB1 mutations. CONCLUSIONS:: These data provide important clinical and molecular characteristics of lung adenocarcinomas from Chinese patients.
