梁乃新;刘雅昕;刘磊;李单青;
LIANG Nai-xin;LIU Ya-xin;LIU Lei;LI Shan-qing;Department of Thoracic Surgery,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College;

• 1:中国医学科学院北京协和医学院北京协和医院胸外科

摘要(Abstract)：

目的研究中国非小细胞肺癌患者PIK3CA基因与其他致癌基因共突变现象及特点。方法 2009年9月至2012年4月全国25家医院病理证实为非小细胞肺癌并进行基因突变检测的患者纳入本研究。收集和分析9个基因位点数据,包括PIK3CA E9、PIK3CA E20、KRAS E2、KRAS E3、BRAF,以及EGFR E18、E19、E20、E21。结果在纳入研究的5125例患者中,有161例(3.14%)存在多个突变,其中77例存在PIK3CA突变,包括50例E9突变和27例E20突变。与PIK3CA共存的其他致癌基因突变位点包括KRAS E2(11例)、KRAS E3(1例)、BRAF(2例)、EGFR E18(4例)、EGFR E20(5例)、EGFR E21(28例)和EGFR E19缺失突变(37例)。在存在PIK3CA共突变的病例中,E9与E20相比,更容易产生共突变现象;与EGFR E20相比,更易与EGFR E21的L858R型突变共存。在PIK3CA E20突变中,H1047R型突变较H1047L型更为常见。与PIK3CA共突变的KRAS突变经常出现在E2的G12位点。BRAF V600E突变也存在与PIK3CA共突变的倾向。结论 PIK3CA是中国非小细胞肺癌常见的共突变致癌基因,其E9与E20突变相互排斥,但均可与其他致癌基因同时存在。其在肺癌发生发展中的作用和对患者预后的意义有待进一步研究。
Objective To investigate the co-mutation of PIK3 CA gene and other oncogenes in non-small cell lung cancer( NSCLC) patients in China. Methods Data were obtained from the patients with pathologically confirmed NSCLC and receiving gene mutation testing in 25 hospitals in China between September 2009 and April 2012. Nine genetic loci were tested and analyzed,including PIK3 CA E9,PIK3 CA E20,KRAS E2,KRAS E3,BRAF,and EGFR( E18,E19,E20,E21). Results A total of 5125 patients were included in this study,of which 161( 3. 14%) had multiple mutations,including 77 with mutations in PIK3 CA,50 in E9 and the other 27 in E20. The other oncogene mutations coexisting with PIK3 CA mutations included KRAS E2( 11 cases),KRAS E3( 1 case),BRAF( 2 cases),EGFR E18( 4 cases),EGFR E20( 5 cases),EGFR E21( 28 cases),and EGFR E19 deletions( 37 cases). Among mutations in PIK3 CA,E9 was more likely than E20 to have coexisting mutations,also more likely to coexist with EGFR E21 L858 R than EGFR E20; whereasamong mutations in PIK3 CA E20,H1047 R was more common than H1047 L. Mutations in KRAS coexisting with PIK3 CA appeared mostly in E2 G12 locus. Mutations in BRAF V600 E were also inclined to coexist with PIK3 CA. Conclusions PIK3 CA might tend to appear concurrently with other oncogene mutations in Chinese NSCLC patients,while mutations in PIK3 CA E9 and E20 are mutually exclusive. Further research is need to reveal the significance of coexistence of PIK3 CA and other oncogene mutations in NSCLC and its impact on patient outcome.

关键词(KeyWords)： PIK3CA;致癌基因;突变;非小细胞肺癌
PIK3CA;oncogene;mutation;non-small cell lung cancer

Abstract:

Keywords:

基金项目(Foundation): 教育部科学技术研究重大项目(311037);; 北京协和医院青年基金(2010116)

作者(Authors): 梁乃新;刘雅昕;刘磊;李单青;
LIANG Nai-xin;LIU Ya-xin;LIU Lei;LI Shan-qing;Department of Thoracic Surgery,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College;

参考文献(References)：

• [1]Fukuoka M,Wu YL,Thongprasert S,et al.Biomarker analyses and final overall survival results from a phase III,randomized,open-label,first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia(IPASS)[J].J Clin Oncol,2011,29:2866-2874.
• [2]Lynch TJ,Bell DW,Sordella R,et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib[J].N Engl J Med,2004,350:2129-2139.
• [3]Paez JG,Janne PA,Lee JC,et al.EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy[J].Science,2004,304:1497-1500.
• [4]Shigematsu H,Lin L,Takahashi T,et al.Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers[J].J Natl Cancer Inst,2005,97:339-346.
• [5]Maemondo M,Inoue A,Kobayashi K,et al.Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR[J].N Engl J Med,2010,362:2380-2388.
• [6]Martin P,Leighl NB,Tsao MS,et al.KRAS mutations as prognostic and predictive markers in non-small cell lung cancer[J].J Thorac Oncol,2013,8:530-542.
• [7]Paik PK,Arcila ME,Fara M,et al.Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations[J].J Clin Oncol,2011,29:2046-2051.
• [8]Papadimitrakopoulou V.Development of PI3K/AKT/m TOR pathway inhibitors and their application in personalized therapy for non-small-cell lung cancer[J].J Thorac Oncol,2012,7:1315-1326.
• [9]Samuels Y,Wang Z,Bardelli A,et al.High frequency of mutations of the PIK3CA gene in human cancers[J].Science,2004,304:554.
• [10]Miled N,Yan Y,Hon WC,et al.Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit[J].Science,2007,317:239-242.
• [11]Yamamoto H,Shigematsu H,Nomura M,et al.PIK3CA mutations and copy number gains in human lung cancers[J].Cancer Res,2008,68:6913-6921.
• [12]Kawano O,Sasaki H,Okuda K,et al.PIK3CA gene amplification in Japanese non-small cell lung cancer[J].Lung Cancer,2007,58:159-160.
• [13]Drilon A,Rekhtman N,Ladanyi M,et al.Squamous-cell carcinomas of the lung:emerging biology,controversies,and the promise of targeted therapy[J].Lancet Oncol,2012,13:e418-e426.
• [14]Engelman JA.Targeting PI3K signalling in cancer:opportunities,challenges and limitations[J].Nat Rev Cancer,2009,9:550-562.
• [15]Courtney KD,Corcoran RB,Engelman JA.The PI3K pathway as drug target in human cancer[J].J Clin Oncol,2010,28:1075-1083.
• [16]Liu P,Cheng H,Roberts TM,et al.Targeting the phosphoinositide 3-kinase pathway in cancer[J].Nat Rev Drug Discov,2009,8:627-644.
• [17]Agoulnik IU,Hodgson MC,Bowden WA,et al.INPP4B:the new kid on the PI3K block[J].Oncotarget,2011,2:321-328.
• [18]Ihle NT,Paine-Murrieta G,Berggren MI,et al.The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts[J].Mol Cancer Ther,2005,4:1349-1357.
• [19]Bendell JC,Rodon J,Burris HA,et al.Phase I,dose-escalation study of BKM120,an oral pan-Class I PI3K inhibitor,in patients with advanced solid tumors[J].J Clin Oncol,2012,30:282-290.
• [20]Ihle NT,Lemos R,Jr.,Wipf P,et al.Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance[J].Cancer Res,2009,69:143-150.
• [21]Reungwetwattana T,Weroha SJ,Molina JR.Oncogenic pathways,molecularly targeted therapies,and highlighted clinical trials in non-small-cell lung cancer(NSCLC)[J].Clin Lung Cancer,2012,13:252-266.
• [22]Pal I,Mandal M.PI3K and Akt as molecular targets for cancer therapy:current clinical outcomes[J].Acta Pharmacol Sin,2012,33:1441-1458.
• [23]Janku F,Wheler JJ,Naing A,et al.PIK3CA mutation H1047R is associated with response to PI3K/AKT/m TOR signaling pathway inhibitors in early-phase clinical trials[J].Cancer Res,2013,73:276-284.
• [24]Gadgeel SM,Wozniak A.Preclinical rationale for PI3K/Akt/m TOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer[J].Clin Lung Cancer,2013,14:322-332.
• [25]Faber AC,Wong KK,Engelman JA.Differences underlying EGFR and HER2 oncogene addiction[J].Cell Cycle,2010,9:851-852.
• [26]Donev IS,Wang W,Yamada T,et al.Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer[J].Clin Cancer Res,2011,17:2260-2269.
• [27]Shimizu T,Tolcher AW,Papadopoulos KP,et al.The clinical effect of the dual-targeting strategy involving PI3K/AKT/m TOR and RAS/MEK/ERK pathways in patients with advanced cancer[J].Clin Cancer Res,2012,18:2316-2325.
• [28]Chaft JE,Arcila ME,Paik PK,et al.Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling[J].Mol Cancer Ther,2012,11:485-491.
• [29]Endoh H,Yatabe Y,Kosaka T,et al.PTEN and PIK3CA expression is associated with prolonged survival after gefitinib treatment in EGFR-mutated lung cancer patients[J].J Thorac Oncol,2006,1:629-634.
• [30]Li G,Luo X,He J,et al.A novel liquidchip platform for simultaneous detection of 70 alleles of DNA somatic mutations on EGFR,KRAS,BRAF and PIK3CA from formalin-fixed and paraffin-embedded slides containing tumor tissue[J].Clin Chem Lab Med,2011,49:191-195.
• [31]Ludovini V,Bianconi F,Pistola L,et al.Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer[J].J Thorac Oncol,2011,6:707-715.
• [32]Karachaliou N,Mayo C,Costa C,et al.KRAS mutations in lung cancer[J].Clin Lung Cancer,2013,14:205-214.
• [33]Janku F,Tsimberidou AM,Garrido-Laguna I,et al.PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/m TOR axis inhibitors[J].Mol Cancer Ther,2011,10:558-565.
• [34]Di Nicolantonio F,Arena S,Tabernero J,et al.Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus[J].J Clin Invest,2010,120:2858-2866.