p16、RASSF1A基因甲基化与中国人群肺癌发生 及被动吸烟关系的研究
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摘要
目的探讨p16、RASSF1A基因甲基化与肺癌发生及被动吸烟的关系。方法采用Meta分析法研究p16、RASSF1A基因甲基化与中国人群肺癌发生与香烟烟雾暴露的关系;采用焦磷酸测序法检测被动吸烟对小鼠肺组织中p16、RASSF1A基因甲基化程度的影响。结果 (1) Meta分析结果显示,中国肺癌吸烟患者中p16基因甲基化频率显著高于肺癌不吸烟患者(OR=3.77,95%CI:1.88～7.58),差异具有统计学意义(P <0.05);RASSF1A基因甲基化频率显著高于肺癌不吸烟患者(OR=4.59,95%CI:1.39～15.15),差异具有统计学意义(P <0.05);(2)被动吸烟小鼠不同剂量组均未检测出p16和RASSF1A基因甲基化。结论中国人群肺癌患者中p16和RASSF1A基因甲基化高度相关,吸烟造成p16和RASSF1A基因甲基化与肺癌易感性相关;被动吸烟对小鼠p16、RASSF1A基因甲基化的程度未造成影响。
Objective To determine the association between p16, RASSF1 A gene methylation and lung cancer occurrence and passive smoking. Methods Meta-analysis was used to study the association between methylation of p16 and RASSF1 A gene and exposure to cigarette smoke in Chinese population. The effect of passive smoking on the methylation of p16 and RASSF1 A genes in the lung tissue of mice was determined by pyrosequencing. Results(1) Meta-analysis showed that the frequency of p16 gene methylation in Chinese lung cancer smoking patients was significantly higher than that in the non-smokers with lung cancer, OR = 3.77, 95%CI: 1.88-7.58, with significant difference(P < 0.05). The frequency of RASSF1 A gene methylation was significantly higher than that of non-smokers with lung cancer, OR = 4.59, 95%CI: 1.39-15.15, with significant difference(P < 0.05);(2) No methylation of the p16 and RASSF1 A genes was detected in passive smoking mice in different dose groups. Conclusion The methylation of p16 and RASSF1 A gene is highly correlated in lung cancer patients in China. The methylation of p16 and RASSF1 A gene is associated with lung cancer susceptibility to smoking. Cigarette exposure has no effect on the degree of methylation of p16 and RASSF1 A genes in mice.
Objective To determine the association between p16, RASSF1 A gene methylation and lung cancer occurrence and passive smoking. Methods Meta-analysis was used to study the association between methylation of p16 and RASSF1 A gene and exposure to cigarette smoke in Chinese population. The effect of passive smoking on the methylation of p16 and RASSF1 A genes in the lung tissue of mice was determined by pyrosequencing. Results(1) Meta-analysis showed that the frequency of p16 gene methylation in Chinese lung cancer smoking patients was significantly higher than that in the non-smokers with lung cancer, OR = 3.77, 95%CI: 1.88-7.58, with significant difference(P < 0.05). The frequency of RASSF1 A gene methylation was significantly higher than that of non-smokers with lung cancer, OR = 4.59, 95%CI: 1.39-15.15, with significant difference(P < 0.05);(2) No methylation of the p16 and RASSF1 A genes was detected in passive smoking mice in different dose groups. Conclusion The methylation of p16 and RASSF1 A gene is highly correlated in lung cancer patients in China. The methylation of p16 and RASSF1 A gene is associated with lung cancer susceptibility to smoking. Cigarette exposure has no effect on the degree of methylation of p16 and RASSF1 A genes in mice.
引文
[1]Wan Q,Rong S,Si W,et al. Cancer statistics in China,2015[J]. Ca Cancer J Clin,2016,66:115-132.
[2]Scesnaite A,Jarmalaite S,Mutanen P,et al. Similar DNA methylation pattern in lung tumours from smokers and never-smokers with second-hand tobacco smoke exposure[J]. Mutagenesis,2012,27(4):423-429.
[3]Wang W,Feng X,Duan X,et al. Establishment of two data mining models of lung cancer screening based on three gene promoter methylations combined with telomere damage[J]. Int J Biol Markers,2017,32(1):141-146.
[4]刘加洪. DNA甲基转移酶在吸烟者肺腺癌p16基因启动子甲基化中的作用机制研究[D].青岛:青岛大学,2016.
[5]杨振华. 28个肿瘤相关基因启动子Cp G岛甲基化及转录与非小细胞肺癌的相关性的研究[D].上海:复旦大学,2004.
[6]Marsit CJ,Kim DH,Liu M,et al. HyPermethylation of RASSF1A and BLU tulllor suppressor genes in non-small cell lung cancer:Implieations for tobacco smoking during adolescence[J]. Int J Cancer,2005,114(2):219-223.
[7]Yanagawa N,Tamura G,Oizumi H,et al. Inverse correlation between EGFR mutation and FHIT,RASSF1A and RUNX3 methylation in lung adenocarcinoma:Relation with smoking status[J]. Anticancer Res,2011,31(4):1211-1214.
[8]万玲玲,贺宇彤,李玉雪,等. P16基因甲基化和P53抗体在非小细胞肺癌血清中的表达[J].河北医药,2017,39(12):1783-1787.
[9]孙楠,张林,刘永煜,等.痰液脱落细胞中p16基因和RASSF1A基因甲基化与周边型非小细胞肺癌关系的研究[J].现代生物医学进展,2012,12(13):2503-2510,2548.
[10]亢春彦,王丹丹,汤少鹏,等.痰标本FHIT、P16、MGMT、RASSF1A、APC基因甲基化在肺癌诊断中的作用[J].临床与实验病理学杂志,2011,27(8):869-873.
[11]张晨烨.多个抑癌基因启动子CpG岛甲基化与肺癌关系的研究[D].杭州:浙江大学,2011.
[12]李仲琪.循环DNA p16基因启动子区甲基化检测在非小细胞肺癌早期诊断中的意义[D].滨州:滨州医学院,2010.
[13]陈浩. GSTM1及CYP1A1基因多态与P16基因甲基化与肺癌关系的研究[D].合肥:安徽医科大学,2009.
[14]孔云明. CYP1A1基因多态及血浆抑癌基因甲基化与肺癌关系的研究[D].合肥:安徽医科大学,2008.
[15]陶文虎,金永堂,于在诚,等. p16基因甲基化对非小细胞肺癌发病的影响[J].癌症进展,2007,1(4):393-397,403.
[16]汪亚松,金永堂,薛绍礼,等. P16基因甲基化和GSTM1基因多态性与非小细胞肺癌易感性研究[J].现代预防医学,2007,1(7):1207-1209,1212.
[17]刘明,刘俊峰,刘兵,等.痰标本p16和MGMT基因甲基化对肺癌的诊断价值[J].肿瘤,2006,1(11):1020-1023.
[18]张志学,张林. ASC和p16基因启动子甲基化与非小细胞肺癌发生发展的关系[J].中国现代医学杂志,2006,1(9):1338-1340,1344.
[19]周安燕. FHIT、MGMT和RASSF1A基因启动子甲基化在肺癌诊断中的价值[D].郑州:郑州大学,2014.
[20]张卉,张树才,张宗德,等. RASSF1A基因甲基化与非小细胞肺癌预后的相关性研究[J].中国肺癌杂志,2010,13(4):311-316.
[21]彭再梅,山长婷,王惠芳.诱导痰RASSF1A,p16和DAPK基因启动子区甲基化在肺癌诊断中的价值[J].中南大学学报(医学版),2010,35(3):247-253.
[22]Lin Q,Geng J,Ma K,et al. RASSF1A,APC,ESR1,ABCB1 and HOXC9,but not p16INK4A,DAPK1,PTEN and MT1G genes were frequently methylated in the stageⅠnon-small cell lung cancer in China[J]. J Cancer Res Clin Oncol,2009,135(12):1675-1684.
[23]Hsu HS,Chen TP,Hung CH,et al. Characterization of a multiple epigenetic marker panel for lung cancer detection and risk assessment in plasma[J]. Cancer,2007,110(9):2019-2026.
[24]Wu W,Yang SF,Liu FF,et al. Association between p16promoter methylation and thyroid cancer risk:A metaanalysis[J]. Asian Pac J Cancer Prev,2015,16(16):7111-7115.
[25]Dammann RH,Richter AM,Jiménez AP,et al. Impact of natural compounds on DNA methylation levels of the tumor suppressor gene RASSF1A in cancer[J]. Int J Mol Sci,2017,18(10):E2160.
[26]Huang T,Chen X,Hong Q,et al. Meta-analyses of gene methylation and smoking behavior in non-small cell lung cancer patients[J]. Sci Rep,2015,10(5):88-97.
[27]Ivorra C,Fraga MF,Bayón GF,et al. DNA methylation patterns in newborns exposed to tobacco in utero[J]. J Transl Med,2015,13:25.
[28]Maccani JZ,Koestler DC,Houseman EA,et al. Placental DNA methylation alterations associated with maternal tobacco smoking at the RUNX3 gene are also associated with gestational age[J]. Epigenomics,2013,5(6):619-630.
[29]Joubert BR,H?berg SE,Nilsen RM,et al. 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy.Environ[J]. Environ Health Perspect,2012,120(10):1425-1431.
[30]Markunas CA,Xu Z,Harlid S,et al. Identification of DNA methylation changes in newborns related to maternal smoking during pregnancy. Environ[J]. Environ Health Perspect,2014,122(10):1147-1153.
[31] Schwender K,Holtk?tter H,Johann KS,et al. Sudden infant death syndrome:exposure to cigarette smoke leads to hypomethylation upstream of the growth factor independent 1(GFI1)gene promoter[J]. Forensic Sci Med Pathol,2016,12(4):399-406.
[32]Rotroff DM,Joubert BR,Marvel SW,et al. Maternal smoking impacts key biological pathways in newborns through epigenetic modification in utero[J]. BMC Genom,2016,17(1):976.
[2]Scesnaite A,Jarmalaite S,Mutanen P,et al. Similar DNA methylation pattern in lung tumours from smokers and never-smokers with second-hand tobacco smoke exposure[J]. Mutagenesis,2012,27(4):423-429.
[3]Wang W,Feng X,Duan X,et al. Establishment of two data mining models of lung cancer screening based on three gene promoter methylations combined with telomere damage[J]. Int J Biol Markers,2017,32(1):141-146.
[4]刘加洪. DNA甲基转移酶在吸烟者肺腺癌p16基因启动子甲基化中的作用机制研究[D].青岛:青岛大学,2016.
[5]杨振华. 28个肿瘤相关基因启动子Cp G岛甲基化及转录与非小细胞肺癌的相关性的研究[D].上海:复旦大学,2004.
[6]Marsit CJ,Kim DH,Liu M,et al. HyPermethylation of RASSF1A and BLU tulllor suppressor genes in non-small cell lung cancer:Implieations for tobacco smoking during adolescence[J]. Int J Cancer,2005,114(2):219-223.
[7]Yanagawa N,Tamura G,Oizumi H,et al. Inverse correlation between EGFR mutation and FHIT,RASSF1A and RUNX3 methylation in lung adenocarcinoma:Relation with smoking status[J]. Anticancer Res,2011,31(4):1211-1214.
[8]万玲玲,贺宇彤,李玉雪,等. P16基因甲基化和P53抗体在非小细胞肺癌血清中的表达[J].河北医药,2017,39(12):1783-1787.
[9]孙楠,张林,刘永煜,等.痰液脱落细胞中p16基因和RASSF1A基因甲基化与周边型非小细胞肺癌关系的研究[J].现代生物医学进展,2012,12(13):2503-2510,2548.
[10]亢春彦,王丹丹,汤少鹏,等.痰标本FHIT、P16、MGMT、RASSF1A、APC基因甲基化在肺癌诊断中的作用[J].临床与实验病理学杂志,2011,27(8):869-873.
[11]张晨烨.多个抑癌基因启动子CpG岛甲基化与肺癌关系的研究[D].杭州:浙江大学,2011.
[12]李仲琪.循环DNA p16基因启动子区甲基化检测在非小细胞肺癌早期诊断中的意义[D].滨州:滨州医学院,2010.
[13]陈浩. GSTM1及CYP1A1基因多态与P16基因甲基化与肺癌关系的研究[D].合肥:安徽医科大学,2009.
[14]孔云明. CYP1A1基因多态及血浆抑癌基因甲基化与肺癌关系的研究[D].合肥:安徽医科大学,2008.
[15]陶文虎,金永堂,于在诚,等. p16基因甲基化对非小细胞肺癌发病的影响[J].癌症进展,2007,1(4):393-397,403.
[16]汪亚松,金永堂,薛绍礼,等. P16基因甲基化和GSTM1基因多态性与非小细胞肺癌易感性研究[J].现代预防医学,2007,1(7):1207-1209,1212.
[17]刘明,刘俊峰,刘兵,等.痰标本p16和MGMT基因甲基化对肺癌的诊断价值[J].肿瘤,2006,1(11):1020-1023.
[18]张志学,张林. ASC和p16基因启动子甲基化与非小细胞肺癌发生发展的关系[J].中国现代医学杂志,2006,1(9):1338-1340,1344.
[19]周安燕. FHIT、MGMT和RASSF1A基因启动子甲基化在肺癌诊断中的价值[D].郑州:郑州大学,2014.
[20]张卉,张树才,张宗德,等. RASSF1A基因甲基化与非小细胞肺癌预后的相关性研究[J].中国肺癌杂志,2010,13(4):311-316.
[21]彭再梅,山长婷,王惠芳.诱导痰RASSF1A,p16和DAPK基因启动子区甲基化在肺癌诊断中的价值[J].中南大学学报(医学版),2010,35(3):247-253.
[22]Lin Q,Geng J,Ma K,et al. RASSF1A,APC,ESR1,ABCB1 and HOXC9,but not p16INK4A,DAPK1,PTEN and MT1G genes were frequently methylated in the stageⅠnon-small cell lung cancer in China[J]. J Cancer Res Clin Oncol,2009,135(12):1675-1684.
[23]Hsu HS,Chen TP,Hung CH,et al. Characterization of a multiple epigenetic marker panel for lung cancer detection and risk assessment in plasma[J]. Cancer,2007,110(9):2019-2026.
[24]Wu W,Yang SF,Liu FF,et al. Association between p16promoter methylation and thyroid cancer risk:A metaanalysis[J]. Asian Pac J Cancer Prev,2015,16(16):7111-7115.
[25]Dammann RH,Richter AM,Jiménez AP,et al. Impact of natural compounds on DNA methylation levels of the tumor suppressor gene RASSF1A in cancer[J]. Int J Mol Sci,2017,18(10):E2160.
[26]Huang T,Chen X,Hong Q,et al. Meta-analyses of gene methylation and smoking behavior in non-small cell lung cancer patients[J]. Sci Rep,2015,10(5):88-97.
[27]Ivorra C,Fraga MF,Bayón GF,et al. DNA methylation patterns in newborns exposed to tobacco in utero[J]. J Transl Med,2015,13:25.
[28]Maccani JZ,Koestler DC,Houseman EA,et al. Placental DNA methylation alterations associated with maternal tobacco smoking at the RUNX3 gene are also associated with gestational age[J]. Epigenomics,2013,5(6):619-630.
[29]Joubert BR,H?berg SE,Nilsen RM,et al. 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy.Environ[J]. Environ Health Perspect,2012,120(10):1425-1431.
[30]Markunas CA,Xu Z,Harlid S,et al. Identification of DNA methylation changes in newborns related to maternal smoking during pregnancy. Environ[J]. Environ Health Perspect,2014,122(10):1147-1153.
[31] Schwender K,Holtk?tter H,Johann KS,et al. Sudden infant death syndrome:exposure to cigarette smoke leads to hypomethylation upstream of the growth factor independent 1(GFI1)gene promoter[J]. Forensic Sci Med Pathol,2016,12(4):399-406.
[32]Rotroff DM,Joubert BR,Marvel SW,et al. Maternal smoking impacts key biological pathways in newborns through epigenetic modification in utero[J]. BMC Genom,2016,17(1):976.