在我國，每年約有40萬人死于肺癌,，在各類癌癥引起的死亡中高居榜首,。肺腺癌是肺癌的各種亞類中最常見的類型，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肺癌的臨床診斷和預后有著重要的意義,。近日，國際肺癌研究協(xié)會舉辦的專業(yè)學術期刊Journal of Thoracic Oncology在線發(fā)表了生化與細胞所季紅斌研究組與復旦大學腫瘤醫(yī)院合作開展的最新研究成果,，報道了中國肺腺癌人群中熱點基因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胞的轉(zhuǎn)移,。表皮生長因子EGFR是介導細胞生長信號的重要分子，并且在臨床上攜帶該基因突的肺癌患者對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,。KRAS是EGFR通路下游的重要信號分子，對MAPK通路有著直接的調(diào)節(jié)作用,。上述三個基因在西方肺癌人群中有著相當比例的突變率,，在亞洲包括韓國和日本肺癌人群中也有一定研究,。我國的肺癌人群中LKB1，EGFR和KRAS突變的總體特征尚缺乏較為全面的認識,。
生化與細胞所季紅斌課題組聯(lián)合復旦大學腫瘤醫(yī)院陳海泉主任領導的胸外科研究室對中國肺腺癌人群中重要的基因突變進行了篩查,。他們篩查的結果發(fā)現(xiàn)LKB1在中國肺腺癌人群中的突變率為6.9%，而且LKB1突變主要來自吸煙患者,。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）,，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,，在中國肺腺癌人群中發(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83.8%,，提示該類肺腺癌人群具有高度的EGFR突變傾向,，并且可能作為TKIs小分子藥物治療的重點人群。這些工作為全面而深入地揭示中國肺癌人群的基因突變譜奠定了一個良好的基礎,。
該項工作得到了國家科技部,、國家自然科學基金委、中科院及上海市科委的經(jīng)費支持,。(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.
