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Relationship between the Mutations of Epidermal Growth Factor Receptor Gene and k-ras Gene and the Clinicopathological Features of Non-small Cell Lung Cancers
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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. -
Key words:
- non-small cell lung cancers /
- epidermal growth factor receptor /
- k-ras /
- mutation
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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 
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