非小细胞肺癌EGFR、KRAS、ALK基因突变与不同转移器官分布的相关性研究进展

^{150086 哈尔滨，哈尔滨医科大学附属第二医院肿瘤内科, Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Chinaa,}

邓立力 (LiLi DENG): moc.621@rotcodgned

邓立力, Lili DENG, E-mail: moc.621@rotcodgned

邓立力 (LiLi DENG): moc.621@rotcodgned

Received 2017 Dec 28; Revised 2018 Feb 10; Accepted 2018 Mar 20.

Abstract

肺癌是我国恶性肿瘤的首位死亡疾病，据统计大约57%的肺癌患者就诊时已经出现了远处转移，临床预后较差。抗肺癌转移是当前治疗晚期转移性肺癌的新方向和思路。既往研究表明肿瘤的生物学改变在一定程度上能够影响肿瘤的转移行为和侵袭扩散模式，而目前的基础及临床研究尚未阐明导致肺癌相关信号转导途径中发生特异性器官转移的分子机制，有关驱动基因突变与器官转移之间相关性的研究也较为罕见。本篇综述旨在对近几年有关非小细胞肺癌表皮生长因子受体（epidermal growth factor receptor, EGFR）、间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）、Kristen鼠肉瘤病毒原癌基因同源体（V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue, KRAS）驱动基因表达的特点以及与转移器官分布之间相关性的文献进行小结。

Keywords: 转移, 肺肿瘤, EGFR, ALK, KRAS

Abstract

Lung cancer is the leading cause of morbidity and mortality of malignant diseases in China. Approximately 57% lung cancer patients harbored distant metastases at initial diagnosis which is relevant to poor outcomes. The research strategy of anti-lung cancer metastasis now has became the new treatment directions and thoughts for lung cancer treatment. Previous studies have shown that changes in the corresponding driving genes on different signaling pathways may be related to the transfer of different organs, and the biological alteration of tumor to some extent can affect the metastatic behavior and metastatic pattern of tumor. However, current clinical and basic studies have not elucidated the molecular mechanism of the specific distant organ metastasis in the pathway of lung cancer related signal transduction, clinical research on the correlation between gene mutation and organ transfer specificity is also relatively rare. This review aims to summarize the characteristics of the expression of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) in non-small cell lung cancer, and the correlation between the distribution of metastatic organs.

Keywords: Metastasis, Lung neoplasms, EGFR, ALK, KRAS

Abstract

肺癌是居于我国第一位的恶性肿瘤致死性疾病，受限于早期诊断的局限，以及高转移性的生物学特点，大部分肺癌患者就诊时已经出现了远处转移，失去早期手术治疗的机会¹]。肺癌常见远处转移部位包括脑、骨、肝脏、肾上腺和肺²]。虽然局部治疗和化疗甚至靶向治疗能够在一定程度上改善转移性病变的治疗应答率，但是不同器官转移的肺癌患者预后差异仍然很大，目前针对不同器官转移进行特异性治疗的研究也较罕见。随着以奥西替尼为代表的第三代靶向药物的应用，推动了我国肺癌诊疗进入精准治疗3.0时代。研究者对肺癌分子生物学的研究越来越深入，逐渐认识到肺癌远处转移是一个涉及多基因调控、多信号传导通路共同参与的复杂过程³]。不同信号通路上相应驱动基因的改变在一定程度上能够影响肿瘤的转移行为和侵袭扩散模式。但是目前关于驱动基因突变与器官转移之间的相关性研究较为罕见，尚无统一定论。进一步认识非小细胞肺癌（non-small cell lung cancer, NSCLC）驱动基因突变的临床特征以及和特异性器官转移模式之间的相关性或许能够提供一些更有效的治疗策略以提高晚期转移性肺癌患者的预后，最大限度地改善患者生活质量，延长生存期。本篇综述旨在对近几年国内外关于NSCLC表皮生长因子受体（epidermal growth factor receptor, EGFR）、间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）、Kristen鼠肉瘤病毒原癌基因同源体（V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue, KRAS）驱动基因表达的特点以及与转移器官分布之间相关性的文献进行小结。

References

1. Chen W, Zheng R, Baade PD, et al Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–132. doi: 10.3322/caac.21338.] [[PubMed][Google Scholar]
2. Sanchez de Cos Escuin J, Abal Arca J, Melchor Iniguez R, et al Tumor, node and metastasis classification of lung cancer-M1a versus M1b--analysis of M descriptors and other prognostic factors. Lung Cancer. 2014;84(2):182–189. doi: 10.1016/j.lungcan.2014.02.006.] [[PubMed][Google Scholar]
3. Kitano H, Chung JY, Ylaya K, et al Profiling of phospho-AKT, phospho-mTOR, phospho-MAPK and EGFR in non-small cell lung cancer. J Histochem Cytochem. 2014;62(5):335–346. doi: 10.1369/0022155414523022.] [[Google Scholar]
4. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapⅡ) Am J Cancer Res. 2015;5(9):2892–2911.
5. Taillibert S, Le Rhun EEpidemiology of brain metastases. Cancer Radiother. 2015;19(1):3–9. doi: 10.1016/j.canrad.2014.11.001.] [[PubMed][Google Scholar]
6. Chen Y, Peng W, Huang Y, et al Significance of serum neuron-specific enolase before treatment in predicting brain metastases and prognosis of advanced non-small cell lung cancer. Zhonghua Zhong Liu Za Zhi. 2015;37(7):508–511.陈燕, 彭伟, 黄艳芳, et al. 治疗前血清神经元特异性烯醇化酶水平在预测晚期非小细胞肺癌脑转移及预后中的意义中华肿瘤杂志 2015;37(7):508–511. doi: 10.3760/cma.j.issn.0253-3766.2015.07.006.] [[PubMed][Google Scholar]
7. Guan J, Chen M, Xiao N, et al EGFR mutations are associated with higher incidence of distant metastases and smaller tumor size in patients with non-small-cell lung cancer based on PET/CT scan. Med Oncol. 2016;33(1):1. doi: 10.1007/s12032-015-0714-8.] [[PubMed][Google Scholar]
8. Li L, Luo S, Lin H, et al Correlation between EGFR mutation status and the incidence of brain metastases in patients with non-small cell lung cancer. J Thorac Dis. 2017;9(8):2510–2520. doi: 10.21037/jtd.2017.07.57.] [[Google Scholar]
9. Li H, Cao J, Zhang X, et al Correlation between status of epidermal growth factor receptor mutation and distant metastases of lung adenocarcinoma upon initial diagnosis based on 1, 063 patients in China. Clin Exp Metastasis. 2017;34(1):63–71. doi: 10.1007/s10585-016-9822-x.] [[PubMed][Google Scholar]
10. Takano K, Kinoshita M, Takagaki M, et al Different spatial distributions of brain metastases from lung cancer by histological subtype and mutation status of epidermal growth factor receptor. Neuro Oncol. 2016;18(5):716–724. doi: 10.1093/neuonc/nov266.] [[Google Scholar]
11. Hsu F, De Caluwe A, Anderson D, et al EGFR mutation status on brain metastases from non-small cell lung cancer. Lung Cancer. 2016;96:101–107. doi: 10.1016/j.lungcan.2016.04.004.] [[PubMed][Google Scholar]
12. Breindel JL, Haskins JW, Cowell EP, et al EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis. Cancer Res. 2013;73(16):5053–5065. doi: 10.1158/0008-5472.can-12-3775.] [[Google Scholar]
13. Singh M, Garg N, Venugopal C, et al STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation. Oncotarget. 2015;6(29):27461–27477. doi: 10.18632/oncotarget.4742.] [[Google Scholar]
14. Fujimoto D, Ueda H, Shimizu R, et al Features and prognostic impact of distant metastasis in patients with stage Ⅳ lung adenocarcinoma harboring EGFR mutations: importance of bone metastasis. Clin Exp Metastasis. 2014;31(5):543–551. doi: 10.1007/s10585-014-9648-3.] [[PubMed][Google Scholar]
15. Confavreux CB, Girard N, Pialat JB, et al Mutational profiling of bone metastases from lung adenocarcinoma: results of a prospective study (POUMOS-TEC) Bonekey Rep. 2014;3:580. doi: 10.1038/bonekey.2014.75.] [[Google Scholar]
16. Weilbaecher KN, Guise TA, McCauley LKCancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11(6):411–425. doi: 10.1038/nrc3055.] [[Google Scholar]
17. Larsen AK, Ouaret D, El Ouadrani K, et al Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol Ther. 2011;131(1):80–90. doi: 10.1016/j.pharmthera.2011.03.012.] [[PubMed][Google Scholar]
18. Doebele RC, Lu X, Sumey C, et al Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer. Cancer. 2012;118(18):4502–4511. doi: 10.1002/cncr.27409.] [[Google Scholar]
19. Togashi Y, Masago K, Kubo T, et al Association of diffuse, random pulmonary metastases, including miliary metastases, with epidermal growth factor receptor mutations in lung adenocarcinoma. Cancer. 2011;117(4):819–825. doi: 10.1002/cncr.25618.] [[PubMed][Google Scholar]
20. Enomoto Y, Takada K, Hagiwara E, et al Distinct features of distant metastasis and lymph node stage in lung adenocarcinoma patients with epidermal growth factor receptor gene mutations. Respir Invest. 2013;51(3):153–157. doi: 10.1016/j.resinv.2013.02.004.] [[PubMed][Google Scholar]
21. Peters S, Camidge DR, Shaw AT, et al Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9):829–838. doi: 10.1056/NEJMoa1704795.] [[PubMed][Google Scholar]
22. Park J, Yamaura H, Yatabe Y, et al Anaplastic lymphoma kinase gene rearrangements in patients with advanced-stage non-small-cell lung cancer: CT characteristics and response to chemotherapy. Cancer Med. 2014;3(1):118–123. doi: 10.1002/cam4.172.] [[Google Scholar]
23. Choi H, Paeng JC, Kim DW, et al Metabolic and metastatic characteristics of ALK-rearranged lung adenocarcinoma on FDG PET/CT. Lung Cancer. 2013;79(3):242–247. doi: 10.1016/j.lungcan.2012.11.021.] [[PubMed][Google Scholar]
24. Tian G, Zhao X, Nie J, et al Clinical characteristics associated with non-small-cell lung cancer harboring ALK rearrangements in Chinese patients. Future Oncol. 2016;12(10):1243–1249. doi: 10.2217/fon.15.361.] [[PubMed][Google Scholar]
25. Zhou J, Yao H, Zhao J, et al Cell block samples from malignant pleural effusion might be valid alternative samples for anaplastic lymphoma kinase detection in patients with advanced non-small-cell lung cancer. Histopathology. 2015;66(7):949–954. doi: 10.1111/his.12560.] [[PubMed][Google Scholar]
26. Chen G, Chen X, Zhang Y, et al A large, single-center, real-world study of clinicopathological characteristics and treatment in advanced ALK-positive non-small-cell lung cancer. Cancer Med. 2017;6(5):953–961. doi: 10.1002/cam4.1059.] [[Google Scholar]
27. Cserepes M, Ostoros G, Lohinai Z, et al Subtype-specific KRAS mutations in advanced lung adenocarcinoma: a retrospective study of patients treated with platinum-based chemotherapy. Eur J Cancer. 2014;50(10):1819–1828. doi: 10.1016/j.ejca.2014.04.001.] [[PubMed][Google Scholar]
28. Martin P, Leighl NB, Tsao MS, et al KRAS mutations as prognostic and predictive markers in non-small cell lung cancer. J Thorac Oncol. 2013;8(5):530–542. doi: 10.1097/JTO.0b013e318283d958.] [[PubMed][Google Scholar]
29. Sorich MJ, Wiese MD, Rowland A, et al Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015;26(1):13–21. doi: 10.1093/annonc/mdu378.] [[PubMed][Google Scholar]
30. Yaeger R, Cowell E, Chou JF, et al RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer. Cancer. 2015;121(8):1195–1203. doi: 10.1002/cncr.29196.] [[Google Scholar]
31. Zhao N, Wilkerson MD, Shah U, et al Alterations of LKB1 and KRAS and risk of brain metastasis: comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma. Lung Cancer. 2014;86(2):255–261. doi: 10.1016/j.lungcan.2014.08.013.] [[Google Scholar]
32. Liu W, Monahan KB, Pfefferle AD, et al LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma. Cancer Cell. 2012;21(6):751–764. doi: 10.1016/j.ccr.2012.03.048.] [[Google Scholar]
33. Lohinai Z, Klikovits T, Moldvay J, et al KRAS-mutation incidence and prognostic value are metastatic site-specific in lung adenocarcinoma: poor prognosis in patients with KRAS mutation and bone metastasis. Sci Rep. 2017;7:39721. doi: 10.1038/srep39721.] [[Google Scholar]
34. Schweiger T, Hegedus B, Nikolowsky C, et al EGFR, BRAF and KRAS status in patients undergoing pulmonary metastasectomy from primary colorectal carcinoma: a prospective follow-up study. Ann Surg Oncol. 2014;21(3):946–954. doi: 10.1245/s10434-013-3386-7.] [[PubMed][Google Scholar]
35. El-Deiry WS, Vijayvergia N, Xiu J, et al Molecular profiling of 6, 892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites. Cancer Biol Ther. 2015;16(12):1726–1737. doi: 10.1080/15384047.2015.1113356.] [[Google Scholar]
36. Bittner N, Baliko Z, Sarosi V, et al Bone Metastases and the EGFR and KRAS mutation status in lung adenocarcinoma--The results of three year retrospective analysis. Pathol Oncol Res. 2015;21(4):1217–1221. doi: 10.1007/s12253-015-9955-2.] [[PubMed][Google Scholar]
37. Hoshino A, Costa-Silva B, Shen TL, et al Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–335. doi: 10.1038/nature15756.] [[Google Scholar]

非小细胞肺癌<em>EGFR</em>、<em>KRAS</em>、<em>ALK</em>基因突变与不同转移器官分布的相关性研究进展

Abstract

Abstract

References