修回日期: 2016-06-01
接受日期: 2016-06-03
在线出版日期: 2016-06-28
结直肠癌(colorectal cancer, CRC)是常见的恶性肿瘤之一, 随着我国经济发展和人民生活水平的不断提高, 生活方式及饮食结构的改变, CRC的发病率呈逐年上升趋势. CRC的治疗一直备受国内外学者的关注, 靶向治疗被认为是目前治疗转移CRC最理想的方案, 而KRAS基因的突变与CRC的靶向治疗有着密切的关联. 因此, 明确KRAS基因的突变对表皮生长因子受体单抗治疗CRC有重要意义. 本文主要从KRAS基因结构与功能、KRAS基因的突变和异质性对表皮生长因子受体单抗治疗CRC的影响作用进行阐述.
核心提示: 结直肠癌(colorectal cancer, CRC)的靶向治疗是目前治疗转移性CRC最理想的方案, 而KRAS基因的突变与靶向治疗有着密切的关联. 本文主要对KRAS基因结构与功能、KRAS基因的突变和异质性对EGFR单抗治疗CRC的影响作用进行了较为全面阐述.
引文著录: 张惠锋, 王昆华. KRAS基因的突变状态对EGFR单抗治疗结直肠癌的影响. 世界华人消化杂志 2016; 24(18): 2850-2855
Revised: June 1, 2016
Accepted: June 3, 2016
Published online: June 28, 2016
Colorectal cancer is one of the most common malignant tumors. With the development of economy and the improvement of living standard in China, which have resulted in great changes in lifestyle and eating habits, the incidence of colorectal cancer has increased year by year. Among all treatments currently available, targeted therapy is considered to be the most ideal treatment for metastatic colorectal cancer. KRAS mutation is closely related to the efficacy of targeted therapy for colorectal cancer. Thus, it is important to clarify the KRAS mutation status before targeted therapy is considered. This paper mainly elaborates the effect of KRAS mutation status on the efficacy of epidermal growth factor receptor monoclonal antibody treatment of colorectal cancer with regard to the structure and function of KRAS gene, KRAS mutations and heterogeneity.
- Citation: Zhang HF, Wang KH. Effect of KRAS mutation status on efficacy of EGFR monoclonal antibody treatment in colorectal cancer. Shijie Huaren Xiaohua Zazhi 2016; 24(18): 2850-2855
- URL: https://www.wjgnet.com/1009-3079/full/v24/i18/2850.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i18.2850
结直肠癌(colorectal cancer, CRC)是全球范围内最为常见的恶性肿瘤之一, 2012年CRC新增发病例数分别位列男性和女性的第3、2位[1,2]. 我国随着经济发展和人民生活水平的不断提高, 生活方式及饮食结构的改变, CRC的发病率呈逐年上升趋势, 因而对他的治疗一直受到大家的关注[3]. 随着靶向药物表皮生长因子受体(epidermal growth factor receptor, EGFR)单抗的成功应用[4], CRC的治疗进入了靶向治疗时代, 然而EGFR单抗的有效性受其下游KRAS基因状态的影[5-11]. 本文就KRAS基因的突变对EGFR单抗治疗CRC效果的影响作一综述.
KRAS基因是RAS基因家族的主要成员之一, 位于EGFR信号通路的下游. RAS基因最先发现是在Harvery鼠肉瘤病毒和Kirsten鼠肉瘤病毒中, 随后, 研究人员相继在大鼠、小鼠、人类的基因组上发现了同源的RAS基因[12-14]. 目前研究发现RAS家族的主要成员分别为: HRAS、KRAS和NRAS, 其中KRAS与人类肿瘤发生的关系最为密切[15,16]. KRAS基因位于人染色体的12p12, 共有5个外显子(包括4个编码外显子和1个非编码外显子), 共同编码189个氨基酸组成的RAS蛋白[17,18], RAS蛋白又名p21蛋白, 分子量为21 kDa.
RAS蛋白在功能上与G蛋白相似, 除了具有与鸟苷酸结合的能力外, 自身还具有弱GTPase活性. RAS蛋白属于膜结合型蛋白, 当其与二磷酸鸟苷结合时为非活性状态, 而当与三磷酸鸟苷结合时为活性状态. KRAS基因作为EGFR信号通路的下游基因, 就像体内一个"开关", 当接受到外界传来的信号时, 可以激活下游的信号通路(主要为RAS/MAPK和RAS/PIK3/AKT通路), 从而调控细胞生长、增殖、分化等重要生理功能[19-21].
近年来随着靶向药物逐渐应用于肿瘤的临床治疗, CRC的靶向治疗也向前迈出了重要的一步, 靶向治疗模式被认为是目前治疗转移性CRC最理想的方案(该治疗方案明显延长了转移性CRC患者的生存时间). 治疗转移性CRC的靶向药物: EGFR单抗(如西妥昔单抗和帕尼单抗)的治疗效果与KRAS基因的突变状态有重要关系. 突变型的KRAS无需EGFR接收信号能够自动活化该通路并启动下游信号的转导, 因此, 只有野生型KRAS基因的患者才能从EGFR单抗中获益, 而突变型的患者则不能. KRAS基因的突变发生在CRC恶变的早期, 以点突变为主, 90%以上的突变位于2号外显子的第12、13位密码子和3号外显子的第61位密码子, 也有研究发现在KRAS基因的第59、117等密码子有突变存在[22-25].
Karapetis等[26]通过对394例接受西妥昔单抗治疗的转移性CRC患者研究发现有42.3%的患者存在KRAS基因突变. 对KRAS野生型和突变型患者同时给予西妥昔单抗治疗后, KRAS野生型患者的无进展, 存活时间明显延长, 而KRAS突变型患者与没有接受西妥昔单抗治疗的患者在存活时间上没有显著. Amado等[27]为了验证KRAS基因的状态对帕尼单抗治疗转移性CRC患者的影响, 采用RT-PCR检测了427例CRC患者的第12和13密码子的7个突变位点(Gly12Asp、Gly12Ala、Gly12Val、Gly12Ser、Gly12Arg、Gly12Cys、Gly13Asp), 结果发现43%CRC患者有KRAS基因突变. KRAS野生型组在用了帕尼单抗治疗后比KRAS突变型组无进展, 存活时间明显延长. KRAS野生型组中位生存时间为12.3 wk, 但KRAS突变型组的中位生存时间只有7.3 wk, 且该组患者对帕尼单抗治疗后的反应率为0%. 其他学者研究结果显示与上述一致, 当CRC患者KRAS基因为野生型时, 对西妥昔单抗治疗敏感, 而当KRAS基因发生突时, 则对西妥昔单抗治疗不敏感[27-33]. 因此, KRAS基因的状态对EGFR单抗治疗的敏感性有着重要意义, 在决定使用西妥昔单抗靶向治疗之前, 首先应检测KRAS基因的突变状态, 以决定患者是否适合使用指针的方能使用抗EGFR抗体治疗[34-38].
由于CRC在不同组织部位的发展速度不一, 导致由KRAS基因的突变时产生的CRC原发灶与转移灶、肿瘤不同区域之间的异质性. Baldus等[39]采用测序的方法, 分别检测了KRAS基因在CRC原发灶(分别在中心位置和周边的不同空间位置取3个样本)、转移灶、原发灶瘤内的突变情况, 发现KRAS基因在CRC原发灶的突变率为41%, CRC原发灶瘤内KRAS基因突变的异质性为8%, CRC原发灶与转移灶之间KRAS基因的异质性为10%, CRC原发灶与淋巴结之间的KRAS基因的异质性为31%. Watanabe等[40]的研究得到了与上述研究一致的结果, KRAS基因在原发灶的突变率为34.9%, CRC原发灶与转移灶之间的KRAS基因的异质性为11.6%. 为了研究CRC原发灶与不同转移灶之间KRAS基因的异质性, Kim等[41]对143位韩国人的KRAS基因的第12、13、61密码子在不同突变情况进行了分析, 结果显示CRC原发灶与转移灶之间KRAS基因总的异质性为17.5%. 尽管远处转移的器官不同, 但是各个转移灶和CRC原发灶之间的异质性没有差异, CRC原发灶与肝、肺、腹膜、淋巴结、卵巢转移灶之间的异质性分别为10.6%、32.4%、13.3%、11.8%、18.2%. 但也有研究报道CRC原发灶与转移灶之间KRAS基因的突变情况一致, 没有KRAS基因突变的异质性存在[42,43]. 由于CRC的KRAS基因存在原发灶与转移灶之间的异质性, 因此容易导致EGFR单抗的耐药; 同时CRC的KRAS基因存在不同空间位置的异质性, CRC某一个区域KRAS基因的状态并不能代表整个肿瘤KRAS基因的状态, KRAS基因突变的检测可能是假阴性, 因此也会影响EGFR单抗对CRC的治疗[44-49].
目前CRC可通过手术切除、化疗、放疗、靶向治疗等多种方式进行治疗, EGFR单抗药物的出现对治疗转移性CRC具有里程碑的意义, 相比传统化疗药物有明显优势, 但同时他也存在一些不足之处. 如当CRC患者存在KRAS基因的突变时, 对EGFR单抗治疗的反应较差; KRAS基因的突变在CRC原发灶与转移灶之间存在异质性时, 采用EGFR单抗治疗易产生耐药和复发. 因而, 提高EGFR单抗的疗效, 减少CRC患者的耐药和复发, 需要我们进一步深入的研究.
结直肠癌(colorectal cancer, CRC)是常见的恶性肿瘤之一, 其治疗一直备受国内外学者的关注, 靶向治疗被认为是当前治疗转移性CRC最理想的方案, 而KRAS基因的突变与CRC的靶向治疗有着密切的关联, 因此, 明确KRAS基因的突变状态对EGFR单抗治疗CRC有重要意义.
刘克辛, 教授, 大连医科大学临床药理学教研室
目前靶向药物治疗转移性CRC被认为最理想的方式, 但KRAS基因突变的异质性会影响靶向药物的效果, 如何克服肿瘤异质性防止肿瘤复发, 亟待大家进一步研究.
由于CRC在不同组织部位的发展速度不一, 导致KRAS基因的突变在CRC原发灶与转移灶、肿瘤内的不同区域之间产生异质性. Baldus等检测了KRAS基因在CRC原发灶、转移灶、原发灶瘤内的突变情况, 发现KRAS基因在原发灶与转移灶之间KRAS基因的异质性为10%, CRC原发灶与淋巴结之间的KRAS基因的异质性为31%.
本文主要介绍了KRAS基因结构与功能, 较为全面、深入的总结了KRAS基因的突变和异质性对EGFR单抗治疗CRC的影响作用.
由于CRC的KRAS基因存在原发灶与转移灶之间的异质性, 容易导致EGFR单抗耐药. 因此克服CRC的异质性, 对防止肿瘤的复发、延长生存期具有重要意义.
EGFR单抗: 即表皮生长因子受体单克隆抗体, 属肿瘤靶向治疗药物, 通过竞争性的抑制内源性配体, 阻断其与胞外受体相关酶的磷酸化, 进而阻断其下游的信号传导通路, 起到直接抑制肿瘤细胞生长作用. 主要用于CRC、非小细胞肺癌等恶性实体瘤的治疗.
本文提出KRAS基因的突变与CRC的靶向治疗有着密切的关联, 并就KRAS基因的突变状态对EGFR单抗治疗CRC效果的进行了较为深入、详尽的综述. 选题有应用意义, 具有一定的科学性.
手稿来源: 自由投稿
学科分类: 胃肠病学和肝病学
手稿来源地: 云南省
同行评议报告分类
A级 (优秀): 0
B级 (非常好): 0
C级 (良好): 0
D级 (一般): 0
E级 (差): 0
编辑:于明茜 电编:闫晋利
| 1. | Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64:104-117. [PubMed] [DOI] |
| 2. | Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7-30. [PubMed] [DOI] |
| 3. | Li M, Gu J. Changing patterns of colorectal cancer in China over a period of 20 years. World J Gastroenterol. 2005;11:4685-4688. [PubMed] [DOI] |
| 4. | Ishikawa T, Uetake H, Sugihara K. [Anti-EGFR antibody therapy for colorectal cancer]. Nihon Rinsho. 2012;70:2152-2158. [PubMed] |
| 5. | Li XX, Liang L, Huang LY, Cai SJ. Standard chemotherapy with cetuximab for treatment of colorectal cancer. World J Gastroenterol. 2015;21:7022-7035. [PubMed] [DOI] |
| 6. | Li X, Pezeshkpour G, Phan RT. KRAS mutation status impacts diagnosis and treatment decision in a patient with two colon tumours: a case report. J Clin Pathol. 2015;68:83-85. [PubMed] [DOI] |
| 7. | Shan L, Li M, Ma J, Zhang H. PCR-based assays versus direct sequencing for evaluating the effect of KRAS status on anti-EGFR treatment response in colorectal cancer patients: a systematic review and meta-analysis. PLoS One. 2014;9:e107926. [PubMed] [DOI] |
| 8. | Kishiki T, Ohnishi H, Masaki T, Ohtsuka K, Ohkura Y, Furuse J, Sugiyama M, Watanabe T. Impact of genetic profiles on the efficacy of anti-EGFR antibodies in metastatic colorectal cancer with KRAS mutation. Oncol Rep. 2014;32:57-64. [PubMed] [DOI] |
| 9. | Therkildsen C, Bergmann TK, Henrichsen-Schnack T, Ladelund S, Nilbert M. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis. Acta Oncol. 2014;53:852-864. [PubMed] [DOI] |
| 10. | Yu S, Xiao X, Lu J, Qian X, Liu B, Feng J. Colorectal cancer patients with low abundance of KRAS mutation may benefit from EGFR antibody therapy. PLoS One. 2013;8:e68022. [PubMed] [DOI] |
| 11. | Tougeron D, Cortes U, Ferru A, Villalva C, Silvain C, Tourani JM, Levillain P, Karayan-Tapon L. Epidermal growth factor receptor (EGFR) and KRAS mutations during chemotherapy plus anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer. Cancer Chemother Pharmacol. 2013;72:397-403. [PubMed] [DOI] |
| 12. | Chang EH, Gonda MA, Ellis RW, Scolnick EM, Lowy DR. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proc Natl Acad Sci USA. 1982;79:4848-4852. [PubMed] [DOI] |
| 13. | DeFeo D, Gonda MA, Young HA, Chang EH, Lowy DR, Scolnick EM, Ellis RW. Analysis of two divergent rat genomic clones homologous to the transforming gene of Harvey murine sarcoma virus. Proc Natl Acad Sci USA. 1981;78:3328-3332. [PubMed] [DOI] |
| 14. | Ellis RW, DeFeo D, Furth ME, Scolnick EM. Mouse cells contain two distinct ras gene mRNA species that can be translated into a p21 onc protein. Mol Cell Biol. 1982;2:1339-1345. [PubMed] [DOI] |
| 15. | Hall A, Marshall CJ, Spurr NK, Weiss RA. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1. Nature. 1983;303:396-400. [PubMed] [DOI] |
| 16. | Murray MJ, Cunningham JM, Parada LF, Dautry F, Lebowitz P, Weinberg RA. The HL-60 transforming sequence: a ras oncogene coexisting with altered myc genes in hematopoietic tumors. Cell. 1983;33:749-757. [PubMed] [DOI] |
| 17. | Bos JL. Ras oneogenes in human cancer: a review. Cancer Res. 1989;49:4682-4689. |
| 18. | McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773:1263-1284. [PubMed] [DOI] |
| 19. | Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11-22. [PubMed] [DOI] |
| 20. | Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE. 2004;2004:RE13. [PubMed] [DOI] |
| 21. | Li M, Zhang Z, Li X, Ye J, Wu X, Tan Z, Liu C, Shen B, Wang XA, Wu W. Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. Nat Genet. 2014;46:872-876. [PubMed] [DOI] |
| 22. | Gorukmez O, Yakut T, Gorukmez O, Sag SO, Karkucak M, Kanat O. Distribution of KRAS and BRAF Mutations in Metastatic Colorectal Cancers in Turkish Patients. Asian Pac J Cancer Prev. 2016;17:1175-1179. [PubMed] [DOI] |
| 23. | Edkins S, O'Meara S, Parker A, Stevens C, Reis M, Jones S, Greenman C, Davies H, Dalgliesh G, Forbes S. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther. 2006;5:928-932. [PubMed] [DOI] |
| 24. | Janakiraman M, Vakiani E, Zeng Z, Pratilas CA, Taylor BS, Chitale D, Halilovic E, Wilson M, Huberman K, Ricarte Filho JC. Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res. 2010;70:5901-5911. [PubMed] [DOI] |
| 25. | Smith G, Bounds R, Wolf H, Steele RJ, Carey FA, Wolf CR. Activating K-Ras mutations outwith 'hotspot' codons in sporadic colorectal tumours - implications for personalised cancer medicine. Br J Cancer. 2010;102:693-703. [PubMed] [DOI] |
| 26. | Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757-1765. [PubMed] [DOI] |
| 27. | Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634. [PubMed] [DOI] |
| 28. | Tejpar S, Peeters M, Humblet Y, Vermorken JB, De Hertogh G, De Roock W, Nippgen J, von Heydebreck A, Stroh C, Van Cutsem E. Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC), treated with irinotecan(q2w) and escalating doses of cetuximab(q1w): The EVEREST experience (preliminary data). J Clin Oncol. 2008;26:4001. |
| 29. | Van Cutsem E, Nowacki M, Lang I, Cascinu S, Shchepotin I, Maurel J, Rougier P, Cunningham D, Nippgen J and Köhne C. Randomized phase Ⅲ study of irinotecanand 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial. Proc Am Soc Clin Oncol. 2007;25:4000. |
| 30. | Van Cutsem E, Lang I, D'haens G, Moiseyenko V, Zaluski J, Folprecht G, Tejpar S, Kisker O, Stroh C, Rougier P. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer(mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol. 2008;26:2. |
| 31. | Bokemeyer C, Bondarenko I, Hartmann JT. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol. 2008;26:4000. |
| 32. | Smits KM, Cleven AH, Weijenberg MP, Hughes LA, Herman JG, de Bruïne AP, van Engeland M. Pharmacoepigenomics in colorectal cancer: a step forward in predicting prognosis and treatment response. Pharmacogenomics. 2008;9:1903-1916. [PubMed] [DOI] |
| 33. | Ogino S, Meyerhardt JA, Irahara N, Niedzwiecki D, Hollis D, Saltz LB, Mayer RJ, Schaefer P, Whittom R, Hantel A. KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res. 2009;15:7322-7329. [PubMed] [DOI] |
| 34. | Roberts PJ, Stinchcombe TE. KRAS mutation: should we test for it, and does it matter? J Clin Oncol. 2013;31:1112-1121. [PubMed] [DOI] |
| 35. | Kimura T, Okamoto K, Miyamoto H, Kimura M, Kitamura S, Takenaka H, Muguruma N, Okahisa T, Aoyagi E, Kajimoto M. Clinical benefit of high-sensitivity KRAS mutation testing in metastatic colorectal cancer treated with anti-EGFR antibody therapy. Oncology. 2012;82:298-304. [PubMed] [DOI] |
| 36. | Gajate P, Sastre J, Bando I, Alonso T, Cillero L, Sanz J, Caldés T, Díaz-Rubio E. Influence of KRAS p.G13D mutation in patients with metastatic colorectal cancer treated with cetuximab. Clin Colorectal Cancer. 2012;11:291-296. [PubMed] [DOI] |
| 37. | Aubin F, Gill S, Burkes R, Colwell B, Kamel-Reid S, Koski S, Pollett A, Samson B, Tehfe M, Wong R. Canadian Expert Group consensus recommendations: KRAS testing in colorectal cancer. Curr Oncol. 2011;18:e180-e184. [PubMed] |
| 38. | Baldus SE, Schaefer KL, Engers R, Hartleb D, Stoecklein NH, Gabbert HE. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res. 2010;16:790-799. [PubMed] [DOI] |
| 39. | Watanabe T, Kobunai T, Yamamoto Y, Matsuda K, Ishihara S, Nozawa K, Iinuma H, Shibuya H, Eshima K. Heterogeneity of KRAS status may explain the subset of discordant KRAS status between primary and metastatic colorectal cancer. Dis Colon Rectum. 2011;54:1170-1178. [PubMed] [DOI] |
| 40. | Kim MJ, Lee HS, Kim JH, Kim YJ, Kwon JH, Lee JO, Bang SM, Park KU, Kim DW, Kang SB. Different metastatic pattern according to the KRAS mutational status and site-specific discordance of KRAS status in patients with colorectal cancer. BMC Cancer. 2012;12:347. [PubMed] [DOI] |
| 41. | Brannon AR, Vakiani E, Sylvester BE, Scott SN, McDermott G, Shah RH, Kania K, Viale A, Oschwald DM, Vacic V. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol. 2014;15:454. [PubMed] [DOI] |
| 42. | Jo P, König A, Schirmer M, Kitz J, Conradi LC, Azizian A, Bernhardt M, Wolff HA, Grade M, Ghadimi M. Heterogeneity of KRAS Mutation Status in Rectal Cancer. PLoS One. 2016;11:e0153278. [PubMed] [DOI] |
| 43. | He Q, Xu Q, Wu W, Chen L, Sun W, Ying J. Comparison of KRAS and PIK3CA gene status between primary tumors and paired metastases in colorectal cancer. Onco Targets Ther. 2016;9:2329-2335. [PubMed] [DOI] |
| 44. | Dienstmann R, Salazar R, Tabernero J. Overcoming Resistance to Anti-EGFR Therapy in Colorectal Cancer. Am Soc Clin Oncol Educ Book. 2015;e149-e156. [PubMed] [DOI] |
| 45. | Mao C, Wu XY, Yang ZY, Threapleton DE, Yuan JQ, Yu YY, Tang JL. Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases. Sci Rep. 2015;5:8065. [PubMed] [DOI] |
| 46. | Paliogiannis P, Cossu A, Tanda F, Palmieri G, Palomba G. KRAS mutational concordance between primary and metastatic colorectal adenocarcinoma. Oncol Lett. 2014;8:1422-1426. [PubMed] |
| 47. | Lee SY, Haq F, Kim D, Jun C, Jo HJ, Ahn SM, Lee WS. Comparative genomic analysis of primary and synchronous metastatic colorectal cancers. PLoS One. 2014;9:e90459. [PubMed] [DOI] |
| 48. | Li Z, Jin K, Lan H, Teng L. Heterogeneity in primary colorectal cancer and its corresponding metastases: a potential reason of EGFR-targeted therapy failure? Hepatogastroenterology. 2011;58:411-416. [PubMed] |