MGMT基因启动子甲基化与非小细胞肺癌化疗敏感性及预后的关系
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摘要
目的:检测非小细胞肺癌(NSCLC)组织中MGMT基因启动子甲基化状态,并分析MGMT基因启动子甲基化与NSCLC术后辅助化疗敏感性及预后的关系。方法:收集2012年1月～2015年6月在本院普胸外科进行手术并化疗辅助治疗的92例NSCLC患者的肿瘤组织和癌旁非肿瘤组织,采用甲基化特异性PCR(MSP)检测组织中MGMT基因启动子甲基化状态,分析MGMT基因启动子甲基化与患者化疗敏感性及无进展生存期(PFS)、3年总生存率的关系。结果:肿瘤组织中MGMT基因启动子甲基化率39.13%(36/92)高于癌旁非肿瘤组织中MGMT基因启动子甲基化率3.26%(3/92)(P<0.05);MGMT基因启动子甲基化与患者TNM分期、淋巴结转移、肿瘤分化程度有关(P<0.05);甲基化组复发、转移或死亡患者比例高于非甲基化组(P<0.05);甲基化组PFS和3年总生存率低于非甲基化组(P<0.05);多因素COX回归分析显示淋巴结转移和MGMT基因启动子甲基化是影响NSCLC患者预后的独立危险因素。结论:MGMT基因启动子甲基化与NSCLC术后铂类辅助化疗敏感性及预后密切相关,可能是逆转NSCLC铂类化疗敏感性,改善其预后的重要靶点。
Objective: To detect the methylation status of MGMT gene promoter in non-small cell lung cancer(NSCLC), and to analyze the relationship between methylation of MGMT gene promoter and the chemosensitivity and prognosis of adjuvant chemotherapy after NSCLC. Methods: Tumor tissues and adjacent non-tumor tissues of 92 patients with NSCLC who underwent surgery and adjuvant chemotherapy from January 2012 to June 2015 in the thoracic surgery department of our hospital were collected, methylation-specific PCR(MSP) was used to detect the methylation status of MGMT gene promoter in tissues, and the relationship between methylation of MGMT gene promoter and chemosensitivity, progression-free survival(PFS) and 3-year overall survival rate was analyzed. Results: The methylation rate of MGMT gene promoter in cancer tissue was 39.13%(36/92) higher than that in non-cancer tissue 3.26%(3/92)(P<0.05); methylation of MGMT gene promoter was associated with TNM stage, lymph node metastasis and tumor differentiation(P<0.05); the proportion of patients with recurrence, metastasis or death in methylation group was higher than that in non-methylation group(P<0.05); PFS and 3-year overall survival rate in methylated group were lower than those in non-methylated group(P<0.05); multivariate COX regression analysis showed that lymph node metastasis and promoter methylation of MGMT gene were independent risk factors for prognosis of NSCLC patients. Conclusion: MGMT gene promoter methylation is closely related to the chemosensitivity and prognosis of platinum-based adjuvant chemotherapy after NSCLC. It may be an important target to reverse the chemosensitivity of platinum-based chemotherapy and improve the prognosis of NSCLC.
Objective: To detect the methylation status of MGMT gene promoter in non-small cell lung cancer(NSCLC), and to analyze the relationship between methylation of MGMT gene promoter and the chemosensitivity and prognosis of adjuvant chemotherapy after NSCLC. Methods: Tumor tissues and adjacent non-tumor tissues of 92 patients with NSCLC who underwent surgery and adjuvant chemotherapy from January 2012 to June 2015 in the thoracic surgery department of our hospital were collected, methylation-specific PCR(MSP) was used to detect the methylation status of MGMT gene promoter in tissues, and the relationship between methylation of MGMT gene promoter and chemosensitivity, progression-free survival(PFS) and 3-year overall survival rate was analyzed. Results: The methylation rate of MGMT gene promoter in cancer tissue was 39.13%(36/92) higher than that in non-cancer tissue 3.26%(3/92)(P<0.05); methylation of MGMT gene promoter was associated with TNM stage, lymph node metastasis and tumor differentiation(P<0.05); the proportion of patients with recurrence, metastasis or death in methylation group was higher than that in non-methylation group(P<0.05); PFS and 3-year overall survival rate in methylated group were lower than those in non-methylated group(P<0.05); multivariate COX regression analysis showed that lymph node metastasis and promoter methylation of MGMT gene were independent risk factors for prognosis of NSCLC patients. Conclusion: MGMT gene promoter methylation is closely related to the chemosensitivity and prognosis of platinum-based adjuvant chemotherapy after NSCLC. It may be an important target to reverse the chemosensitivity of platinum-based chemotherapy and improve the prognosis of NSCLC.
引文
1 罗猛,刘波,刘迪,等.非小细胞肺癌患者微创切除术后的复发与转移状况研究[J].中国内镜杂志,2017,23(9):42-47.
2 汤山松.血清CYFRA21-1和CEA联合检测诊断非小细胞肺癌的临床研究[J].热带医学杂志,2017,17(12):1626-1628.
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4 Yang X,Han H,De Carvalho DD,et al.Gene body methylation can alter gene expression and is a therapeutic target in cancer[J].Cancer Cell,2014,26(4):577-590.
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9 Wang BH,Li YY,Han JZ,et al.Gene methylation as a powerful biomarker for detection and screening of non-small cell lung cancer in blood[J].Oncotarget,2017,8(19):31692-31704.
10 Chen L,Wang Y,Liu F,et al.A systematic review and meta-analysis:Association between MGMT hypermethylation and the clinicopathological characteristics of non-small-cell lung carcinoma[J].Sci Rep,2018,8(1):1439-1431.
11 Binabaj MM,Bahrami A,ShahidSales S,et al.The prognostic value of MGMT promoter methylation in glioblastoma:A meta-analysis of clinical trials[J].J Cell Physiol,2018,233(1):378-386.
12 田春艳,李馥郁,杨晋,等.吉非替尼联合吉西他滨和顺铂化疗方案治疗晚期非小细胞肺癌临床疗效及对血清肿瘤标志物的影响[J].解放军医药杂志,2018,30(4):25-28.Tian CY,Li FY,Yang J,et al.Clinical efficacy of gefitinib combined with gemcitabine and cisplatin chemotherapy in treatment of patients with advanced non-small cell lung cancer and its effects on serum tumor markers[J].Med Pharm J Chin PLA,2018,30(4):25-28.
13 李瑶,呼群.表观遗传调控与肿瘤耐药[J].现代肿瘤医学,2016,24(2):322-325.
14 吴亚琼,方伟蓉,李运曼.肿瘤多药耐药机制及逆转药物的研究进展[J].药学与临床研究,2016,24(1):43-47.
15 Jürgen Mattern,Eichhorn U,Kaina B,et al.O6-methylguanine-DNA methyltransferase activity and sensitivity to cyclophosphamide and cisplatin in human lung tumor xenografts[J].Int J Cancer,2015,77(6):919-922.
16 骆海军,李丽丽,李伟,等.DNA修复相关基因甲基化与肺癌A549细胞顺铂化疗耐药的相关性研究[J].中华实用诊断与治疗杂志,2014,28(2):122-124.
17 王虹,李丽丽,张吉才,等.5-氮杂-2′脱氧胞苷对肺癌A549/DDP细胞hMLHl,MGMT基因甲基化及其表达的影响[J].现代检验医学杂志,2015,30(3):83-86.
18 Chen C,Hua H,Han C,et al.Prognosis value of MGMT promoter methylation for patients with lung cancer:a meta-analysis[J].Int J Clin Exp Pathol,2015,8(9):11560-11564.
2 汤山松.血清CYFRA21-1和CEA联合检测诊断非小细胞肺癌的临床研究[J].热带医学杂志,2017,17(12):1626-1628.
3 彭胜祖,李晓,王云,等.术后辅助化疗对I期非小细胞肺癌无瘤生存时间的影响[J].中国肺癌杂志,2017,20(7):485-489.
4 Yang X,Han H,De Carvalho DD,et al.Gene body methylation can alter gene expression and is a therapeutic target in cancer[J].Cancer Cell,2014,26(4):577-590.
5 Danam RP,Qian XC,Howell SR,et al.Methylation of selected CpGs in the human O6-methylguanine-DNA methyltransferase promoter region as a marker of gene silencing[J].Mol Carcinog,2015,24(2):85-89.
6 Gu C,Lu J,Cui T,et al.Association between MGMT promoter methylation and non-small cell lung cancer:a meta-analysis[J].Plos One,2013,8(9):601-605.
7 Tanoue LT,Detterbeck FC.New TNM classification for non-small-cell lung cancer[J].Expert Rev Anticancer Ther,2009,9(4):413-423.
8 Yang Z,Li F.O-6-methylguanine-DNA methyltransferase gene promoter methylation and lung cancer risk:A meta-analysis[J].J Cancer Res Ther,2016,12(Supplement):C233-C236.
9 Wang BH,Li YY,Han JZ,et al.Gene methylation as a powerful biomarker for detection and screening of non-small cell lung cancer in blood[J].Oncotarget,2017,8(19):31692-31704.
10 Chen L,Wang Y,Liu F,et al.A systematic review and meta-analysis:Association between MGMT hypermethylation and the clinicopathological characteristics of non-small-cell lung carcinoma[J].Sci Rep,2018,8(1):1439-1431.
11 Binabaj MM,Bahrami A,ShahidSales S,et al.The prognostic value of MGMT promoter methylation in glioblastoma:A meta-analysis of clinical trials[J].J Cell Physiol,2018,233(1):378-386.
12 田春艳,李馥郁,杨晋,等.吉非替尼联合吉西他滨和顺铂化疗方案治疗晚期非小细胞肺癌临床疗效及对血清肿瘤标志物的影响[J].解放军医药杂志,2018,30(4):25-28.Tian CY,Li FY,Yang J,et al.Clinical efficacy of gefitinib combined with gemcitabine and cisplatin chemotherapy in treatment of patients with advanced non-small cell lung cancer and its effects on serum tumor markers[J].Med Pharm J Chin PLA,2018,30(4):25-28.
13 李瑶,呼群.表观遗传调控与肿瘤耐药[J].现代肿瘤医学,2016,24(2):322-325.
14 吴亚琼,方伟蓉,李运曼.肿瘤多药耐药机制及逆转药物的研究进展[J].药学与临床研究,2016,24(1):43-47.
15 Jürgen Mattern,Eichhorn U,Kaina B,et al.O6-methylguanine-DNA methyltransferase activity and sensitivity to cyclophosphamide and cisplatin in human lung tumor xenografts[J].Int J Cancer,2015,77(6):919-922.
16 骆海军,李丽丽,李伟,等.DNA修复相关基因甲基化与肺癌A549细胞顺铂化疗耐药的相关性研究[J].中华实用诊断与治疗杂志,2014,28(2):122-124.
17 王虹,李丽丽,张吉才,等.5-氮杂-2′脱氧胞苷对肺癌A549/DDP细胞hMLHl,MGMT基因甲基化及其表达的影响[J].现代检验医学杂志,2015,30(3):83-86.
18 Chen C,Hua H,Han C,et al.Prognosis value of MGMT promoter methylation for patients with lung cancer:a meta-analysis[J].Int J Clin Exp Pathol,2015,8(9):11560-11564.