在我国，每年约有40万人死于肺癌，在各类癌症引起的死亡中高居榜首。肺腺癌是肺癌的各种亚类中最常见的类型，在每年全球确诊的新增肺癌病患中约占40%。研究肺癌中基因突变对肺癌的临床诊断和预后有着重要的意义。近日，国际肺癌研究协会举办的专业学术期刊Journal of Thoracic Oncology在线发表了生化与细胞所季红斌研究组与复旦大学肿瘤医院合作开展的最新研究成果，报道了中国肺腺癌人群中热点基因LKB1、EGFR和KRAS的突变谱。
LKB1又名STK11 (serine threonine kinase 11)，是丝氨酸苏氨酸激酶家族的成员，并且是家族性黑斑息肉综合症的致病基因。季红斌研究组此前的工作发现抑癌基因LKB1对肿瘤的转移有着重要的影响，其蛋白缺失可显著提高肿瘤细胞的转移。表皮生长因子EGFR是介导细胞生长信号的重要分子，并且在临床上携带该基因突的肺癌患者对抑制酪氨酸激酶的小分子化合物抑制剂（Tyrosine Kinase inhibitors，TKIs）有着很高的响应。KRAS是EGFR通路下游的重要信号分子，对MAPK通路有着直接的调节作用。上述三个基因在西方肺癌人群中有着相当比例的突变率，在亚洲包括韩国和日本肺癌人群中也有一定研究。我国的肺癌人群中LKB1，EGFR和KRAS突变的总体特征尚缺乏较为全面的认识。
生化与细胞所季红斌课题组联合复旦大学肿瘤医院陈海泉主任领导的胸外科研究室对中国肺腺癌人群中重要的基因突变进行了筛查。他们筛查的结果发现LKB1在中国肺腺癌人群中的突变率为6.9%，而且LKB1突变主要来自吸烟患者。LKB1的F354L变异在肺腺癌人群中的比例约为10.5%且均为种系遗传（即从父母遗传而来），其中两例患者的肿瘤组织内F354L变异发生了杂合性缺失，提示该位点在肺癌的发生或发展中可能有着尚待探明的作用。与此同时，在中国肺腺癌人群中发现的EGFR突变率为66.3%，KRAS突变仅为2.3%。在EGFR突变中，较为引人注意的是女性非吸烟患者的突变率高达83.8%，提示该类肺腺癌人群具有高度的EGFR突变倾向，并且可能作为TKIs小分子药物治疗的重点人群。这些工作为全面而深入地揭示中国肺癌人群的基因突变谱奠定了一个良好的基础。
该项工作得到了国家科技部、国家自然科学基金委、中科院及上海市科委的经费支持。(生物谷www.Bioon.net)
生物谷推荐原文出处：
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.
