作者投稿
专家审稿
编辑办公
邮件订阅
RSS
Relationship between the Mutations of Epidermal Growth Factor Receptor Gene and k-ras Gene and the Clinicopathological Features of Non-small Cell Lung Cancers
-
摘要:目的 探讨非小细胞肺癌(non-small cell lung cancers, NSCLC)肿瘤组织中表皮生长因子受体(epidermal growth factor receptor, EGFR)基因及k-ras基因突变与临床病理特征的关系。方法 应用显微切割技术及蝎形探针扩增阻滞突变系统(scorpions amplification refractory mutation system, Scorpions ARMS)检测170例NSCLC石蜡包埋肿瘤组织中EGFR基因第18、19、20和21外显子突变及k-ras基因12、13密码子突变, 统计分析EGFR及k-ras基因突变与不同组织类型NSCLC临床和病理特征的相关性。结果 Scorpions ARMS检测结果显示, 170例NSCLC肿瘤组织中84例存在EGFR突变, 突变检出率为49.4%, 其中39例为EGFR第19外显子缺失改变, 34例为EGFR第21外显子L858R点突变, 3例为EGFR第21外显子L861Q点突变, 4例为EGFR第20外显子插入突变, 2例为EGFR第20外显子S768I点突变, 另外2例为EGFR第20外显子T790M点突变和第21外显子L858R点突变同时存在。170例NSCLC肿瘤组织标本中检测到14例k-ras基因突变, 检出率为8.2%, 均位于12密码子, 其中8例为12CYS点突变, 3例为12ASP点突变, 3例为12VAL点突变。未发现k-ras基因突变与EGFR基因突变发生在同一NSCLC肿瘤组织标本中。腺癌与非腺癌EG-FR基因突变比较差异具有统计学意义(P < 0.001), 突变更常见于腺癌。此外, 比较EGFR基因突变与NSCLC各临床病理因素的关系, 发现EGFR基因突变更常见于女性、不吸烟、肿瘤较小(≤ 3cm)且分化程度较好的NSCLC患者; 然而, k-ras基因突变与患者年龄、性别、吸烟史、肿瘤大小、组织学类型、肿瘤分化程度、淋巴结转移及pTNM分期等均无显著的相关性(P > 0.05)。结论 中国NSCLC患者的EGFR基因突变检出率明显高于其他国家, 且女性、不吸烟、腺癌患者突变率较高; 而k-ras基因突变的检出率很低, 其突变与性别、年龄等临床病理特征无关; EGFR和k-ras基因突变不会同时存在同一患者中。吉非替尼疗效和耐药与EGFR和k-ras基因突变相关。Scorpions ARMS技术可快速、敏感、准确地检测EGFR与k-ras基因突变, 能为临床治疗及预后提供重要信息。Abstract:Objective To investigate the relationship between the mutations of epidermal growth factor receptor(EGFR)gene, k-ras gene and clinicopathological characteristics in Chinese patients with non-small cell lung cancers (NSCLC).Methods Tumor cells were collected by microdissection from paraffin embedded tumor specimens obtained from 170 patients with NSCLC. The genomic DNA was extracted.Mutations of EGFR gene (exons 18, 19, 20, and 21) and k-ras gene (codons 12 and 13) were detected by scorpions amplification refractory mutation system (Scorpions ARMS).Results Somatic mutations were identified involving the tyrosine kinase domain of the EGFR gene in 84 patients (49.4%), which included in-frame deletions of exon 19 (n=39), point mutation of exon 21L858R (n=34), point mutation of exon 21L861Q (n=3), insertions mutations (n=4) and point mutation in exon 20 (n=2), and co-existence of T790M point mutation in exon 20 and L858R point mutations in exon 21 (n=2). k-ras mutations were identified in 14 patients (8.2%), among whom a single-amino-acid substitution in codon 12 were noted in all of them including 8 for 12CYS, 3 for 12ASP, and 3 for 12VAL. Simultaneously harbored EGFR and k-ras gene mutations were not observed in any single NSCLC specimen. Compared adenocarcinoma with non-adenocarcinoma, EGFR mutation rate was statistically significant (P < 0.001) and the former had higher mutation rate. Also, the relationship between EGFR mutations and various clinicopathological factors suggested that the EGFR mutations usually occurred in the female, non-smokers, smaller tumors (≤ 3 cm), and better differentiation. However, there was no association among age, gender, smoking, tumor size, histological types, differentiation grades, lymph node metastasis, pTNM stages and k-ras mutations (P > 0.05).Conclusions The detection rate of EGFR mutation is remarkably higher in China than other countries, especially in non-smoking female patients with adenocarcinoma. The detection rate of k-ras mutation is very low, which is not associated with the clinical features such as gender and age. The efficacy and drug resistance of gefitinib is associated with the mutations of EGFR and k-ras gene. k-ras mutations does not coexist with EGFR mutations. Scorpions ARMS method is a rapid, sensitive, and accurate technology in detecting the mutations of EGFR gene and k-ras gene and can therefore provide useful information for clinical decision-making.
-
Keywords:
- non-small cell lung cancers /
- epidermal growth factor receptor /
- k-ras /
- mutation
-
临床上用131I治疗甲状腺功能亢进(主要指Graves病)方便、安全、有效, 在发达国家已成为治疗Graves病的首选方法, 在国内也已广泛开展。但是这种疗法关键的半衰期的测量需要等待数天时间, 患者治疗前需来院4次, 增加了患者和医生的负担。北京协和医院核医学科康增寿教授在国际上首先发现131I有效半衰期与转换率呈负相关, 并与北京核仪器厂合作研发出了131I有效半衰期测定软件(EHL软件), 将测定时间缩短到24 h。
康增寿教授介绍说, 131I治疗甲亢的4个主要步骤为:测定甲状腺摄取131I率、测定有效半衰期、甲状腺显像估算重量和设计口服剂量。其中有效半衰期测定是指24 h最高摄131I率降至一半时的天数。第1天, 医生需要测定患者2、4、6、24 h的吸碘率, 找出这4个值的最大值。48 h后, 医生需要再次测定患者的吸碘率, 查看吸碘率是否降到了首日最大值的一半。如果没有降到一半, 则需要在72 h后再次测定并比较。以此类推, 直到测定的吸碘率降到一半, 取当时的天数为有效半衰期。用以上传统做法测定131I有效半衰期一般需要5 ~ 7 d, 这是131I治疗甲亢的一大弊病。
根据多年临床经验, 康增寿教授发现摄131I转换率(4 h吸131I率与24 h吸131I率的比值)与有效半衰期间呈负相关。对已治疗的1044例Graves病患者的摄131I转换率和实测有效半衰期进行回顾性总结的结果, 证实了二者间的负相关关系。
康教授根据1044例患者的大样本量分析, 推算出回归方程式为:Y=-4.551X+9.1693, R= -0.664。其中X表示摄131I转换率, Y就是有效半衰期的天数。R=-0.664表示X与Y的相关系数。根据以上公式, 用第1天测定的摄131I转换率就可以直接推算出有效半衰期, 将测定时间缩短至24 h。在北京核仪器厂协助下, 131I治疗甲亢有效半衰期测定软件———EHL软件研发成功, 医生只需将第1天测定的吸碘率输入EHL软件, 就可以立即得到有效半衰期的数值。康教授进一步对300例131I治疗的Graves病患者实测有效半衰期的数值与EHL软件测定值进行比较, 结果证实了EHL软件的科学性与准确性。
EHL软件可在24 h内测出131I治疗的有效半衰期, 为医生和患者节省了120 h, 工作效率提高了4倍, 同时还避免了多次实测的误差, 使数据更加科学有效。目前, EHL软件已在北京协和医院核医学科推广使用, 患者和医生都深深受益。
(北京协和医院宣传处 何帆)
-
![]()
图 3 高分化腺癌组织(103号标本)EGFR基因第21外显子L858R点突变(曲线M1)及第20外显子T790M点突变(曲线M2)
曲线W:野生型扩增曲线; EGFR:同图 1
表 1 非小细胞肺癌组织EGFR和k-ras基因突变与临床病理特征的关系
临床特征 例数 EGFR基因 k-ras基因 突变例数(%) 无突变例数(%) P值* 突变例数(%) 无突变例数(%) P值* 性别 170 男性 86 33 (39. 3) 53 (61. 6) 0. 004 10 (71. 4) 76 (48. 7) 0. 103 女性 84 51 (60. 7) 33 (38. 4) 4 (28. 6) 80 (51. 3) 年龄 170 ≤60 74 36 (42. 9) 38 (44. 2) 0.861 5 (35. 7) 69 (44. 2) 0.538 >60 96 48 (57. 1) 48 (55. 8) 9 (64. 3) 87 (55. 8) 吸烟史 170 有 105 61 (72. 6) 44 (51. 2) 0. 004 6 (42. 9) 99 (63. 5) 0. 129 无 65 23 (27. 4) 42 (48. 8) 8 (57. 1) 0. 117 肿瘤大小(cm) 170 ≤3 70 42 (50. 0) 28 (32. 6) 0. 021 3 (21. 4) 67 (42. 9) 0. 117 >3 100 42 (50. 0) 58 (67. 4) 11 (78. 6) 89 (57. 1) 组织学类型 170 腺癌 136 82 (97. 6) 54 (62. 8) ＜0. 001 10 (71. 4) 126 (80. 8) 0. 483 非腺癌 34 2 (2. 4) 32 (37. 2) 4 (28. 6) 30 (19. 2) 分化程度 170 高分化 67 46 (54. 8) 21 (24. 4) ＜0. 001 4 (28. 6) 63 (40. 4) 0. 386 中-低分化 103 38 (45. 2) 65 (75. 6) 10 (71. 4) 93 (59. 6) 淋巴结转移 170 无 76 43 (51. 2) 33 (38. 4) 0. 093 8 (57. 1) 68 (43. 6) 0. 329 有 94 41 (48. 8) 53 (61. 6) 6 (42. 9) 88 (56. 4) pTNM分期 170 Ⅰ期 65 34 (40. 5) 31 (36. 0) 0. 552 8 (57. 1) 57 (36. 5) 0. 129 Ⅱ-Ⅳ期 105 50 (59. 5) 55 (64. 0) 6 (42. 9) 99 (63. 5) EGFR:表皮生长因子受体; *P值为有无突变病例间的比较 
下载: 导出CSV
-
[1] Travis WD, Brambilla E, Muller-Hermelink HK, et al. World Health Organization classification of tumors.Pathology and genetics tumors of the lung, plrura, thymus and heart [M].Lyon:IARC Press, 2004:12-15.
[2] Jemal A, Siegel R, Ward E, et al.Cancer Statistics, 2006 [J].CA Cancer J Clin, 2006, 56:106-130. DOI: 10.3322/canjclin.56.2.106
[3] Scagliotti GV, Selvaggi G, Novello S, et al.The biology of epidermal growth factor receptor in lung cancer[J].Clin Cancer Res, 2004, 10:4227-4232. DOI: 10.1158/1078-0432.CCR-040007
[4] Fukuoka M, Yano S, Giaccone G, et al.Multiinstitutional randomized phase Ⅱ trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer[J].J Clin Oncol, 2003, 21:2237-2246. DOI: 10.1200/JCO.2003.10.038
[5] Kris MG, Natale RB, Herbst RS, et al.Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer:a randomized trial[J].JAMA, 2003, 290: 2149-2158. DOI: 10.1001/jama.290.16.2149
[6] 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. DOI: 10.1126/science.1099314
[7] Lynch TJ, Bell DW, Sordella R, et al.Activating mutations in the epidermal growth factor recepto runderlying responsiveness of non-small-cell lung cancer to gefitinib[J].N Engl J Med, 2004, 350:2129-2139. DOI: 10.1056/NEJMoa040938
[8] 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. DOI: 10.1093/jnci/dji055
[9] 张静, 梁智勇, 曾瑄, 等.应用蝎形探针扩增阻滞突变系统检测非小细胞肺癌表皮生长因子受体基因突变与病理改变的关系[J].中华病理学杂志, 2008, 37:294- 299. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=zhblx200805002 [10] Graziano SL, Gamble GP, Newman NB, et al.Prognostic significance of k-rascodon 12 mutations in patients with resected stage Ⅰ and Ⅱ non-small-cell lung cancer[J].J Clin Oncol, 1999, 17:668-675. DOI: 10.1200/JCO.1999.17.2.668
[11] Massarelli E, Varella-Garcia M, Tang X, et al.KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer[J].Clin Cancer Res, 2007, 13:2890-2896. DOI: 10.1158/1078-0432.CCR-06-3043
[12] Fujno S, Enokibori T, Tezuka N, et al.A comparison of epidermal growth factor receptor levels and other prognostic parameters in non-small cell lung cancer[J].Eur J Cancer, 1996, 32A, 2070-2074. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=10.1097/CJI.0000000000000300
[13] Bell DW, Lynch TJ, Haserlat SM, et al.Epidermal growth factor receptor mutations and gene amplification in nonsmall-cell lung cancer:molecular analysis of the IDEAL/INTACT gefitinib trials[J].J Clin Oncol, 2005, 23:8081- 8092. DOI: 10.1200/JCO.2005.02.7078
[14] Masaki T, Shiniehi T, Katsuyuki K, et al.The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non small cell lung cancers[J]. Clin Cancer Res, 2005, 11:1167-1173. http://jjco.oxfordjournals.org/cgi/ijlink?linkType=ABST&journalCode=clincanres&resid=11/3/1167
[15] 张晓彤, 李龙芸, 王树兰, 等.吉非替尼治疗晚期非小细胞肺癌疗效观察[J].中华结核和呼吸杂志, 2005, 28:180-183. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=zhjhhhx200503010 [16] Sanford M, Scott LJ.Gefitinib:a review of its use in the treatment of locally advanced/metastatic non-small cell lung cancer[J].Drugs, 2009, 69:2303-2328. DOI: 10.2165/10489100-000000000-00000
[17] Kalikaki A, Koutsopoulos A, Hatzidaki D, et al.Clinical outcome of patients with non-small cell lung cancer receiving front-line chemotherapy according to EGFR and k-ras mutation status[J].Lung Cancer, 2010, 69:110-115. DOI: 10.1016/j.lungcan.2009.09.010
[18] Slebos RJ, Kibbelaar RE, Dalesio O, et al.k-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung[J].N Engl J Med, 1990, 323:561-565. DOI: 10.1056/NEJM199008303230902
[19] Massarelli E, Varella-Garcia M, Tang X, et al.KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer[J].Clin Cancer Res, 2007, 13:2890-2896. DOI: 10.1158/1078-0432.CCR-06-3043
[20] Linardou H, Dahabreh IJ, Kanaloupiti D, et al.Assessment of somatic k-ras mutations as a mechanism associated with resistance to EGFR-targeted agents:a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer[J].Lancet Oncol, 2008, 9:962-972. DOI: 10.1016/S1470-2045(08)70206-7
[21] Kosaka T, Yatabe Y, Endoh H, et al.Mutations of the epidermal growth factor receptor gene in lung cancer:biological and clinical implications[J]. Cancer Res, 2004, 64: 8919-8923. DOI: 10.1158/0008-5472.CAN-04-2818
[22] Planchard D, Loriot Y, Besse B.Impac t of KRAS in standard treatment of non-smallcell lung cancer(NSCLC) patients in 2009:prognostic and predictive value[J].Bull Cancer, 2009, 96:S57-S68.
-
期刊类型引用(16)
1. 张晓丽，刘金苹. 乳腺叶状肿瘤的超声特征分析. 北京医学. 2022(02): 185-187 . 
百度学术
2. 李冬. 不同病理类型乳腺叶状肿瘤的超声图像特征分析. 现代医用影像学. 2021(12): 2319-2322 . 百度学术
3. 王常珺，姚儒，师杰，张晓辉，孙强. 乳腺恶性孤立性纤维性肿瘤两例. 协和医学杂志. 2018(04): 364-366 . 本站查看
4. 王运. 乳腺纤维腺瘤的超声诊断分析. 影像研究与医学应用. 2018(20): 135-136 . 百度学术
5. 宋丹，赵玉哲，曹文庆，张静，王跃欣，巩涛. 乳腺叶状肿瘤临床特点及误诊原因分析. 临床误诊误治. 2017(07): 31-34 . 百度学术
6. 汪林，隋秀芳，李红苗，张杰，叶显俊. 超声在乳腺分叶状肿瘤诊断中的应用. 中国临床保健杂志. 2017(06): 745-748 . 百度学术
7. 丁志颖，黄敏，郭建锋. 比较三阴性乳腺癌与BI-RADS 4A类不典型纤维腺瘤及腺病超声表现. 中国医学影像技术. 2017(12): 1830-1834 . 百度学术
8. 张丹，李燕东，丁奕文，李杨. 乳腺叶状肿瘤的组织结构与声像图表现的相关分析及文献复习. 中华临床医师杂志(电子版). 2016(22): 3463-3465 . 百度学术
9. 高男. 乳腺叶状肿瘤患者的超声诊断价值. 中国民康医学. 2015(17): 47-48 . 百度学术
10. 覃冠平. 乳腺叶状肿瘤的临床病理诊断分析. 中外医疗. 2014(09): 56-57 . 百度学术
11. 霍兰茹，刘佩芳，徐熠琳，李小康，邵真真，朱鹰. 乳腺叶状肿瘤超声表现与病理相关性研究. 中国肿瘤临床. 2014(09): 571-575 . 百度学术
12. 周勇. 乳腺恶性叶状肿瘤30例临床分析. 基层医学论坛. 2013(19): 2566-2567 . 百度学术
13. 贺祎，张忠磊，贺祎，宋晓雨，陈炫龙，刘慧. 巨大乳腺肿瘤的超声诊断价值. 中华临床医师杂志(电子版). 2013(24): 11894-11896 . 百度学术
14. 张建萍，尉继伟，刘治邦，肖来华. 乳腺叶状肿瘤影像诊断及治疗. 实用医技杂志. 2012(07): 706-707 . 百度学术
15. 骆洪浩，彭玉兰，于雷，赵海娜，史岩. 乳腺叶状肿瘤的高频超声声像图分析. 中国医学计算机成像杂志. 2012(03): 255-258 . 百度学术
16. 孝梦甦，朱庆莉，姜玉新，戴晴，李建初，游珊珊，张璟，刘赫. 乳腺恶性叶状肿瘤的临床与超声特征研究. 中华医学超声杂志(电子版). 2012(12): 1083-1088 . 百度学术
其他类型引用(5)
计量
- 文章访问数: 243
- HTML全文浏览量: 115
- PDF下载量: 22
- 被引次数: 21
