TGFBR2基因多态性与晚期NSCLC铂类化疗
|
摘要
背景:绝大多数非小细胞肺癌(non-small cell lung cancer,NSCLC)患者确诊时已属晚期(III或者IV期,约占肺癌总发病率的80%),铂类联合化疗是其标准的一线治疗方案。然而,NSCLC五年存活率低于15%。近年的研究表明,基因标志物可预测肿瘤化疗的预后,如,药物转运、代谢、DNA修复和凋亡相关基因的多态性可预测药物的细胞毒性及药物疗效。迄今的研究表明,转化生长因子受体II (transforming growth factor beta type II receptor, TGFBR2)在细胞增殖和凋亡中起重要作用,推测极有可能影响到铂类药物的预后。
一、TGFBR2基因多态性和NSCLC铂类化疗疗效及毒性反应关联分析
目的: TGFBR2基因多态性与NSCLC铂类化疗疗效和毒副反应的关联及预测分析。
方法:
(一)研究对象:回顾性研究,收集2005年3月至2010年1月收住于上海长海医院、胸科医院和中山医院的初治为铂类化疗的III-IV期NSCLC汉人患者。
(二)疗效、毒性与体力状态评判:患者在接受两个疗程治疗后,按照RECIST标准进行疗效评价,计算疾病控制率(疾病控制和疾病未控制),疾病控制包括完全缓解(CR)、部分缓解(PR)和稳定(SD)患者,疾病未控制为进展(PD);化疗药物的血液和胃肠道毒副反应每周两次进行评估,毒副反应程度按美国国家癌症研究所不良反应分级标准3.0,轻度毒性反应包括0、1和2级毒性反应,严重毒性反应包括3和4级毒性反应。评估由经治医师完成并记录,专人再收集,对经治医师采用双盲方法。
(三)SNP位点选择:采用Haploview软件选择标签TGFBR2 SNP,选点原则为MAF大于0.05,r2大于0.8。
(四)基因分型:用Infinium HD Assay分型技术进行基因分型。
(五)统计分析:SNP多态性与毒性、疗效的关联用非条件逻辑回归(Unconditional logistic regression)进行分析,经性别、年龄、体力状况及治疗方案校正。单点分析:以每个多态性位点(SNP)的突变型纯合子基因型(BB AA)或突变型杂合子基因型(AB),与野生型纯合子基因型(AA )相比较(BB VS AA,或AB VS AA),计算OR值、95%可信区间及p值。多点分析:用PHASE II和Haploview软件对TGFBR2基因SNP进行单倍域(Haplotype block)分析,计算OR值、95%可信区间及p值。校正方法采用Bonfferoni法。
结果:
(一)研究对象的临床特征:
1、病人基本特征:共收集1004例经病理确诊的IIIA-IV期非小细胞肺癌患者,年龄为26-82岁。中位年龄58岁,≤58岁514例,>58岁486例;化疗前PS评分0-1为904例,PS评分2为86例;男性706例,女性297例;IIIA 81例,IIIB 293例,IV 625例;铂-长春瑞滨316例,铂-吉西他滨239例,铂-紫杉醇313例,铂-其它136例。
2、疗效和毒副反应:疾病控制率为81.7%。各种毒性反应:严重贫血3.1%,严重血小板毒性反应3.6%,严重白细胞毒性反应15.2%,严重粒细胞毒性反应12.3%,严重血液总毒性发生率为23.9%,严重胃肠道毒性发生率为8.3%。
(二) SNP选择和分型结果:共选择34个TGFBR2标签SNP位点,rs9844092未能进行分型(MAF = 0),其余位点分型准确率大于99%,重复样本分型一致性为100%。因此,最后进行关联分析的为33个SNP位点。
(三)关联分析结果:
(1)单点分析: TGFBR2基因多态性显著增加重度总毒性反应的风险:女性人群rs2276768 CT VS CC,OR = 3.026,95% CI = 1.741-5.258,p = 0.00008575;TGFBR2基因多态性显著增加重度血液毒性反应风险:女性人群rs2276768 CT VS CC, OR = 4.031,95% CI =
2.171 - 7.482,p = 0.00001004。经Bonfferoni方法校正后,女性人群中rs2276768杂合子CT显著增加总毒性及重度血液毒性反应风险。
(2)单体型分析:根据1004例研究对象的基因型,将TGFBR2的33个SNP分为九个单倍域(Block1-9)。分析显示Block 9 (rs2276768,rs3773663,rs304839和rs2276767)的单体型CGTC相对于TGAC,与疾病控制率负显著相关,OR值0.672,95% CI为0.514-0.879,p=0.004。
二、TGBFBR2 rs2276768单核苷酸多态功能初探
检测104例经铂类治疗的肺癌患者,携带rs2276768变异等位基因CT的个体,其TGFBR2 mRNA相对表达量的平均值相对于野生纯合子CC个体,增加约30.3%,与增加血液毒性风险的预期相一致。
目的:研究TGBBR2基因多态性是否通过影响该基因mRNA表达,影响血液毒性反应。
方法:
(一)研究对象:1004例入组病人中长海医院病人104例。
(二)全血RNA抽提。
(三)定量RT-PCR分析:RNA抽提、定量PCR检测和分析。
结果:
携带rs2276768变异等位基因CT的个体,其TGFBR2 mRNA相对表达量的平均值相对于野生纯合子CC个体,增加约30.3%,与增加疾病控制率和重度血液毒性风险的预期相一致。
小结:
一、单点分析和多点分析结果提示,女性人群中rs2276768杂合子CT显著增加总毒性及重度血液毒性反应的风险,单体型CGTC相对于单体型TGAC(block顺序:rs2276768,rs3773663,rs304839和rs2276767),显著增加疾病未控制率风险。
二、rs2276768杂合子可能通过增加TGFBR2 mRNA表达量,增加血液毒性反应风险。
结论:本次实验首次发现TGFBR2基因多态性和晚期NSCLC铂类化疗疗效和毒性反应显著关联,其中rs2276768杂合子CT显著增加女性严重总毒性和血液毒性反应风险;rs2276768可能通过改变mRNA水平,降低血液毒性风险。上述关联分析结果尚需进行深入的功能验证。
Non-small cell lung cancer (NSCLC) accounts for approximately 80% of such deaths. Most NSCLC patients are diagnosed in the advanced (stage III or IV) stages. Five-year survival rates for NSCLC remain less than 15%. Standard treatment for NSCLC involves chemotherapy with a platinum agent and another cytotoxic agent. Recent clinical studies suggest a large potential for genomic findings in treatment outcome predictions. It is widely recognized that genetic polymorphisms in genes for drug transport, drug metabolizing, DNA repair and apoptosis often play important roles in the variability of cytotoxic chemotherapy toxicity outcomes. In this study, we focused on transforming growth factor, beta receptor II (TGFBR2), being important in cell proliferation and apoptosis.
Purpose: to investigate the association between TGFBR2 polymorphisms and the incidence of adverse events in advanced non-small cell lung cancer (NSCLC) patients receiving first-line platinum-based chemotherapy through mRNA expression.
Patients and Methods: A retrospective pharmacogenetic association study was performed in 1004 Chinese patients with advanced NSCLC receiving platinum-based regimens (including 221 treated with cisplain-navelbine, 195 with cisplatin-gemcitabine, 190 with carboplatin-paclitaxel, and 108 with cisplatin-paclitaxel). Information about grade 3 or 4 overall toxicity, gastrointestinal toxicity (nausea/vomiting) and hematologic toxicity (neutropenia, anemia, thrombocytopenia) was available. 34 tag single nucleotide polymorphisms (SNPs) of TGFBR2 were assessed.
PATIENTS AND METHODS:Study design and patients recruitment. All patients enrolled in the study were Chinese, and had histologically diagnosed stage IIIA-IV NSCLC at Shanghai Chest, Shanghai Zhongshan and Shanghai Changhai Hospitals between March 2005 and January 2010. Patient responses to the treatment were evsluated after first two courses by the Response Evaluation Criteria in Solid Tumors(RECIST) guideline, which classify Patient responses to the treatment were evaluated after first two courses, which classify the responses into four categories: complete response (CR),partial response (PR), stable disease88 (SD), and progressive disease (PD). For the data analysis, CR and PR were combined as responders, and SD and PD were grouped as non-responders. Chemotherapy toxicity was assessed twice weekly and graded according to the National Cancer Institute Common Toxicity Criteria version 3.0. Toxicities included neutropenia, anemia, thrombocytopenia, nausea, and vomiting. Severe hematologic toxicity included grade 3 or 4 neutropenia, anemia, or thrombocytopenia. Severe gastrointestinal toxicity included grade 3 or 4 nausea or vomiting. Severe overall toxicity included grade 3 or 4 hematologic or gastrointestinal toxicity. The complete medical record (including progress notes of the treating oncologist and nurses) was available and reviewed. Investigators were blinded to the genotype status of the patients. Chemotherapy regimens: all patients enrolled in this study were considered to be inoperable, so received first-line platinum-based chemotherapy (Patients receiving definitive chemoradiotherapy were excluded): cisplatin, or carboplatin, both administered, in combination with navelbine, or gemcitabine, or paclitaxel, or docetaxel. Few patients were given other platinum-based treatment. All chemotherapeutic drugs were administered intravenously, and all included patients were treated for two to six cycles. TGFBR2 SNP selection and genotyping: the genotype data of TGFBR2 gene regionfrom the CHB population were downloaded from phase II HapMap SNP database, and tag-SNPs were selected by the Haploview Software, using a minor allele frequency (MAF) cut-off of 0.05 and r threshold of 0.8. Blood samples were obtained in EDTA tubes from patients at the time of re-cruitment. Genomic DNA was extracted using the QIAamp DNA Maxi Kit. All SNPs selected were genotyped using iSelect HD BeadChip (illumina), with quality control criteria as follows: genotyping call rate of SNP>0.95; MAF>0.05; GenCall score>0.2. Therefore, a polymerase chain reaction (PCR)-SNaPshot method was used to supplement Statistical Analysis. The analyses were specified to investigate the relation-ships between TGFBR2 polymorphisms and severe toxicity occurrence, overall and by treatment arm, respectively. Toxicity outcomes were dichotomized by the presence or absence of (i) any grade 3 or 4 overall toxicity, (ii) any grade 3 or 4 hematologic toxicity (including neutropenia, anemia, and thrombocytopenia), and (iii) any grade 3 or 4 gastrointestinal toxicity (nausea/vomiting). We then investigated whether these polymorphisms were associated with severe hematological toxicity, gastrointestinal toxicity, or disease controlled rate among 1004 platinum-based chemotherapy treated advanced NSCLC patients. Single gene polymorphisms correlation analysis has been done. OR, 95% confidence interval and p value were calculated respectively. Each polymorphic loci (SNP) of the mutant homozygous genotype (BB ) or mutant heterozygous mutant genotype (AB), compared with wild homozygous genotype(AA),is represented by BB VS AA or AB VS AA.Adjusting covariates were the
genotyping data of polymorphisms (gender, age at diagnosis, performance status and type of treatment regimen. Statistical analyses used SPSS. Pairwise linkage disequilibrium defined by the four-gamete rule in the Haploview Software. Individual haplotype frequencies were estimated based on the Bayesian algorithm, using the PHASE 2.0 program. Haplotype-toxicity association was evaluated for each block, using SPSS.
Outcome:In this study, 33 tag single nucleotide polymorphisms in TGFBR2 gene were selected except rs9844092 (MAF =0). 1004 patients enrolled in the study. Among the 1004 NSCLC patients. The median age of patients was 58 years (range, 18–82), and there were 706 patients (male) and 297 (female). The majority of patients (62.6%) had stage IV disease. Disease controlled rate was 81.7%, while severe toxicity incidenceincidences were 3.1% (anemia), 3.6% ( thrombocytopenia), 15.2% (leukocytopenia), 12.3 %( agranulocytosis), 23.9% (any grade 3 or 4 hematologic toxicity), and 8.3% (any grade 3 or 4 gastrointestinal toxicity). An association between the variant genotypes of and the risk of severe overall toxicity was aslo observered (rs2228048, CT VS CC, OR= 1.638, 95% CI =1.131 - 2.372, p = 0.00894, among male group; rs2276768, CT VS CC, OR = 3.026, 95%CI = 1.741-5.258, p=0.00008575, among female patient groups.An increased risk was assciated between the variatn genotypes (rs9310940, TT VS GG,OR = 4.85,95%CI=1.503-15.65,p=0.00825, among adenocarcinoma Patient groups.
Conclusion: this study showed TGFBR2 gene polymorphism played a predictive role on clinic outcome in advanced NSCLC patients receiving first-line platinum-based chemotherapy, especially among female patient groups. Furthermore, was associated with hematological toxicity through mRNA expression.
一、TGFBR2基因多态性和NSCLC铂类化疗疗效及毒性反应关联分析
目的: TGFBR2基因多态性与NSCLC铂类化疗疗效和毒副反应的关联及预测分析。
方法:
(一)研究对象:回顾性研究,收集2005年3月至2010年1月收住于上海长海医院、胸科医院和中山医院的初治为铂类化疗的III-IV期NSCLC汉人患者。
(二)疗效、毒性与体力状态评判:患者在接受两个疗程治疗后,按照RECIST标准进行疗效评价,计算疾病控制率(疾病控制和疾病未控制),疾病控制包括完全缓解(CR)、部分缓解(PR)和稳定(SD)患者,疾病未控制为进展(PD);化疗药物的血液和胃肠道毒副反应每周两次进行评估,毒副反应程度按美国国家癌症研究所不良反应分级标准3.0,轻度毒性反应包括0、1和2级毒性反应,严重毒性反应包括3和4级毒性反应。评估由经治医师完成并记录,专人再收集,对经治医师采用双盲方法。
(三)SNP位点选择:采用Haploview软件选择标签TGFBR2 SNP,选点原则为MAF大于0.05,r2大于0.8。
(四)基因分型:用Infinium HD Assay分型技术进行基因分型。
(五)统计分析:SNP多态性与毒性、疗效的关联用非条件逻辑回归(Unconditional logistic regression)进行分析,经性别、年龄、体力状况及治疗方案校正。单点分析:以每个多态性位点(SNP)的突变型纯合子基因型(BB AA)或突变型杂合子基因型(AB),与野生型纯合子基因型(AA )相比较(BB VS AA,或AB VS AA),计算OR值、95%可信区间及p值。多点分析:用PHASE II和Haploview软件对TGFBR2基因SNP进行单倍域(Haplotype block)分析,计算OR值、95%可信区间及p值。校正方法采用Bonfferoni法。
结果:
(一)研究对象的临床特征:
1、病人基本特征:共收集1004例经病理确诊的IIIA-IV期非小细胞肺癌患者,年龄为26-82岁。中位年龄58岁,≤58岁514例,>58岁486例;化疗前PS评分0-1为904例,PS评分2为86例;男性706例,女性297例;IIIA 81例,IIIB 293例,IV 625例;铂-长春瑞滨316例,铂-吉西他滨239例,铂-紫杉醇313例,铂-其它136例。
2、疗效和毒副反应:疾病控制率为81.7%。各种毒性反应:严重贫血3.1%,严重血小板毒性反应3.6%,严重白细胞毒性反应15.2%,严重粒细胞毒性反应12.3%,严重血液总毒性发生率为23.9%,严重胃肠道毒性发生率为8.3%。
(二) SNP选择和分型结果:共选择34个TGFBR2标签SNP位点,rs9844092未能进行分型(MAF = 0),其余位点分型准确率大于99%,重复样本分型一致性为100%。因此,最后进行关联分析的为33个SNP位点。
(三)关联分析结果:
(1)单点分析: TGFBR2基因多态性显著增加重度总毒性反应的风险:女性人群rs2276768 CT VS CC,OR = 3.026,95% CI = 1.741-5.258,p = 0.00008575;TGFBR2基因多态性显著增加重度血液毒性反应风险:女性人群rs2276768 CT VS CC, OR = 4.031,95% CI =
2.171 - 7.482,p = 0.00001004。经Bonfferoni方法校正后,女性人群中rs2276768杂合子CT显著增加总毒性及重度血液毒性反应风险。
(2)单体型分析:根据1004例研究对象的基因型,将TGFBR2的33个SNP分为九个单倍域(Block1-9)。分析显示Block 9 (rs2276768,rs3773663,rs304839和rs2276767)的单体型CGTC相对于TGAC,与疾病控制率负显著相关,OR值0.672,95% CI为0.514-0.879,p=0.004。
二、TGBFBR2 rs2276768单核苷酸多态功能初探
检测104例经铂类治疗的肺癌患者,携带rs2276768变异等位基因CT的个体,其TGFBR2 mRNA相对表达量的平均值相对于野生纯合子CC个体,增加约30.3%,与增加血液毒性风险的预期相一致。
目的:研究TGBBR2基因多态性是否通过影响该基因mRNA表达,影响血液毒性反应。
方法:
(一)研究对象:1004例入组病人中长海医院病人104例。
(二)全血RNA抽提。
(三)定量RT-PCR分析:RNA抽提、定量PCR检测和分析。
结果:
携带rs2276768变异等位基因CT的个体,其TGFBR2 mRNA相对表达量的平均值相对于野生纯合子CC个体,增加约30.3%,与增加疾病控制率和重度血液毒性风险的预期相一致。
小结:
一、单点分析和多点分析结果提示,女性人群中rs2276768杂合子CT显著增加总毒性及重度血液毒性反应的风险,单体型CGTC相对于单体型TGAC(block顺序:rs2276768,rs3773663,rs304839和rs2276767),显著增加疾病未控制率风险。
二、rs2276768杂合子可能通过增加TGFBR2 mRNA表达量,增加血液毒性反应风险。
结论:本次实验首次发现TGFBR2基因多态性和晚期NSCLC铂类化疗疗效和毒性反应显著关联,其中rs2276768杂合子CT显著增加女性严重总毒性和血液毒性反应风险;rs2276768可能通过改变mRNA水平,降低血液毒性风险。上述关联分析结果尚需进行深入的功能验证。
Non-small cell lung cancer (NSCLC) accounts for approximately 80% of such deaths. Most NSCLC patients are diagnosed in the advanced (stage III or IV) stages. Five-year survival rates for NSCLC remain less than 15%. Standard treatment for NSCLC involves chemotherapy with a platinum agent and another cytotoxic agent. Recent clinical studies suggest a large potential for genomic findings in treatment outcome predictions. It is widely recognized that genetic polymorphisms in genes for drug transport, drug metabolizing, DNA repair and apoptosis often play important roles in the variability of cytotoxic chemotherapy toxicity outcomes. In this study, we focused on transforming growth factor, beta receptor II (TGFBR2), being important in cell proliferation and apoptosis.
Purpose: to investigate the association between TGFBR2 polymorphisms and the incidence of adverse events in advanced non-small cell lung cancer (NSCLC) patients receiving first-line platinum-based chemotherapy through mRNA expression.
Patients and Methods: A retrospective pharmacogenetic association study was performed in 1004 Chinese patients with advanced NSCLC receiving platinum-based regimens (including 221 treated with cisplain-navelbine, 195 with cisplatin-gemcitabine, 190 with carboplatin-paclitaxel, and 108 with cisplatin-paclitaxel). Information about grade 3 or 4 overall toxicity, gastrointestinal toxicity (nausea/vomiting) and hematologic toxicity (neutropenia, anemia, thrombocytopenia) was available. 34 tag single nucleotide polymorphisms (SNPs) of TGFBR2 were assessed.
PATIENTS AND METHODS:Study design and patients recruitment. All patients enrolled in the study were Chinese, and had histologically diagnosed stage IIIA-IV NSCLC at Shanghai Chest, Shanghai Zhongshan and Shanghai Changhai Hospitals between March 2005 and January 2010. Patient responses to the treatment were evsluated after first two courses by the Response Evaluation Criteria in Solid Tumors(RECIST) guideline, which classify Patient responses to the treatment were evaluated after first two courses, which classify the responses into four categories: complete response (CR),partial response (PR), stable disease88 (SD), and progressive disease (PD). For the data analysis, CR and PR were combined as responders, and SD and PD were grouped as non-responders. Chemotherapy toxicity was assessed twice weekly and graded according to the National Cancer Institute Common Toxicity Criteria version 3.0. Toxicities included neutropenia, anemia, thrombocytopenia, nausea, and vomiting. Severe hematologic toxicity included grade 3 or 4 neutropenia, anemia, or thrombocytopenia. Severe gastrointestinal toxicity included grade 3 or 4 nausea or vomiting. Severe overall toxicity included grade 3 or 4 hematologic or gastrointestinal toxicity. The complete medical record (including progress notes of the treating oncologist and nurses) was available and reviewed. Investigators were blinded to the genotype status of the patients. Chemotherapy regimens: all patients enrolled in this study were considered to be inoperable, so received first-line platinum-based chemotherapy (Patients receiving definitive chemoradiotherapy were excluded): cisplatin, or carboplatin, both administered, in combination with navelbine, or gemcitabine, or paclitaxel, or docetaxel. Few patients were given other platinum-based treatment. All chemotherapeutic drugs were administered intravenously, and all included patients were treated for two to six cycles. TGFBR2 SNP selection and genotyping: the genotype data of TGFBR2 gene regionfrom the CHB population were downloaded from phase II HapMap SNP database, and tag-SNPs were selected by the Haploview Software, using a minor allele frequency (MAF) cut-off of 0.05 and r threshold of 0.8. Blood samples were obtained in EDTA tubes from patients at the time of re-cruitment. Genomic DNA was extracted using the QIAamp DNA Maxi Kit. All SNPs selected were genotyped using iSelect HD BeadChip (illumina), with quality control criteria as follows: genotyping call rate of SNP>0.95; MAF>0.05; GenCall score>0.2. Therefore, a polymerase chain reaction (PCR)-SNaPshot method was used to supplement Statistical Analysis. The analyses were specified to investigate the relation-ships between TGFBR2 polymorphisms and severe toxicity occurrence, overall and by treatment arm, respectively. Toxicity outcomes were dichotomized by the presence or absence of (i) any grade 3 or 4 overall toxicity, (ii) any grade 3 or 4 hematologic toxicity (including neutropenia, anemia, and thrombocytopenia), and (iii) any grade 3 or 4 gastrointestinal toxicity (nausea/vomiting). We then investigated whether these polymorphisms were associated with severe hematological toxicity, gastrointestinal toxicity, or disease controlled rate among 1004 platinum-based chemotherapy treated advanced NSCLC patients. Single gene polymorphisms correlation analysis has been done. OR, 95% confidence interval and p value were calculated respectively. Each polymorphic loci (SNP) of the mutant homozygous genotype (BB ) or mutant heterozygous mutant genotype (AB), compared with wild homozygous genotype(AA),is represented by BB VS AA or AB VS AA.Adjusting covariates were the
genotyping data of polymorphisms (gender, age at diagnosis, performance status and type of treatment regimen. Statistical analyses used SPSS. Pairwise linkage disequilibrium defined by the four-gamete rule in the Haploview Software. Individual haplotype frequencies were estimated based on the Bayesian algorithm, using the PHASE 2.0 program. Haplotype-toxicity association was evaluated for each block, using SPSS.
Outcome:In this study, 33 tag single nucleotide polymorphisms in TGFBR2 gene were selected except rs9844092 (MAF =0). 1004 patients enrolled in the study. Among the 1004 NSCLC patients. The median age of patients was 58 years (range, 18–82), and there were 706 patients (male) and 297 (female). The majority of patients (62.6%) had stage IV disease. Disease controlled rate was 81.7%, while severe toxicity incidenceincidences were 3.1% (anemia), 3.6% ( thrombocytopenia), 15.2% (leukocytopenia), 12.3 %( agranulocytosis), 23.9% (any grade 3 or 4 hematologic toxicity), and 8.3% (any grade 3 or 4 gastrointestinal toxicity). An association between the variant genotypes of and the risk of severe overall toxicity was aslo observered (rs2228048, CT VS CC, OR= 1.638, 95% CI =1.131 - 2.372, p = 0.00894, among male group; rs2276768, CT VS CC, OR = 3.026, 95%CI = 1.741-5.258, p=0.00008575, among female patient groups.An increased risk was assciated between the variatn genotypes (rs9310940, TT VS GG,OR = 4.85,95%CI=1.503-15.65,p=0.00825, among adenocarcinoma Patient groups.
Conclusion: this study showed TGFBR2 gene polymorphism played a predictive role on clinic outcome in advanced NSCLC patients receiving first-line platinum-based chemotherapy, especially among female patient groups. Furthermore, was associated with hematological toxicity through mRNA expression.
引文
[1] Weinshilboum, R., Inheritance and drug response. N Engl J Med, 2003. 348(6): p. 529-37..
[2] SIDDIK ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22:7265-79.
[3] Bear, W.L. and R.W. Teel, Effects of citrus phytochemicals on liver and lung cytochrome P450 activity and on the in vitro metabolism of the tobacco-specific nitrosamine NNK. Anticancer Res, 2000. 20(5A): p. 3323-9..
[4] Hu, X., et al., Mechanism of differential catalytic efficiency of two polymorphic forms of human glutathione S-transferase P1-1 in the glutathione conjugation of carcinogenic diol epoxide of chrysene. Arch Biochem Biophys, 1997. 345(1): p. 32-8..
[5] Mechanic, L.E., et al., Common genetic variation in TP53 is associated with lung cancer risk and prognosis in African Americans and somatic mutations in lung tumors. Cancer Epidemiol Biomarkers Prev, 2007. 16(2): p. 214-22..
[6] Choi, Y.Y., et al., Comprehensive assessment of P21 polymorphisms and lung cancer risk. J Hum Genet, 2008. 53(1): p. 87-95..
[7] Chen, D., et al., Genetic variants in peroxisome proliferator-activated receptor-gamma gene are associated with risk of lung cancer in a Chinese population. Carcinogenesis, 2008. 29(2): p. 342-50..
[8] Su, L., et al., Genotypes and haplotypes of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer. Carcinogenesis, 2006. 27(5): p. 1024-9..
[9] Sauter, W., et al., Matrix metalloproteinase 1 (MMP1) is associated with early-onset lung cancer. Cancer Epidemiol Biomarkers Prev, 2008. 17(5): p. 1127-35..
[10] Lee, W.K., et al., Polymorphisms in the Caspase7 gene and the risk of lung cancer. Lung Cancer, 2009. 65(1): p. 19-24..
[11] Jang, J.S., et al., Identification of polymorphisms in the Caspase-3 gene and their association with lung cancer risk. Mol Carcinog, 2008. 47(5): p. 383-90..
[12] Suzuki, A., et al., Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death. Oncogene, 2000. 19(10): p. 1346-53..
[13] Yin, J., et al., HapMap-based study of the DNA repair gene ERCC2 and lung cancer susceptibility in a Chinese population. Carcinogenesis, 2009. 30(7): p. 1181-5..
[14] Yin, J., et al., A haplotype encompassing the variant allele of DNA repair gene polymorphism ERCC2/XPD Lys751Gln but not the variant allele of Asp312Asn is associated with risk of lung cancer in a northeastern Chinese population. Cancer Genet Cytogenet, 2007. 175(1): p. 47-51..
[15] Kang, H.G., et al., Polymorphisms in TGF-beta1 gene and the risk of lung cancer. Lung Cancer, 2006. 52(1): p. 1-7..
[16] GALLIHER AJ, NEIL JR, SCHIEMANN WP. Role of transforming growth factor-beta in cancer progression. Future Oncol. 2006;2:743-63.
[17] MEULMEESTER E, TEN DP. The dynamic roles of TGF-beta in cancer. J Pathol. 2011;223:205-18.
[18] Derynck, R., R.J. Akhurst, and A. Balmain, TGF-beta signaling in tumor suppression and cancer progression. Nat Genet, 2001. 29(2): p. 117-29..
[19] Derynck, R. and Y.E. Zhang, Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003. 425(6958): p. 577-84..
[20] Siegel, P.M. and J. Massague, Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer, 2003. 3(11): p. 807-21..
[21] del Re, E., et al., In the absence of type III receptor, the transforming growth factor (TGF)-beta type II-B receptor requires the type I receptor to bind TGF-beta2. J Biol Chem, 2004. 279(21): p. 22765-72..
[22] Souchelnytskyi, S., et al., Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem, 1997. 272(44): p. 28107-15.
[23] Park, K., et al., Genetic changes in the transforming growth factor beta (TGF-beta) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci U S A, 1994. 91(19): p. 8772-6..
[24] Markowitz, S., et al., Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science, 1995. 268(5215): p. 1336-8..
[25] Capocasale, R.J., et al., Reduced surface expression of transforming growth factor beta receptor type II in mitogen-activated T cells from Sezary patients. Proc Natl Acad Sci U S A, 1995. 92(12): p. 5501-5..
[26] Kadin, M.E., et al., Loss of receptors for transforming growth factor beta in human T-cell malignancies. Proc Natl Acad Sci U S A, 1994. 91(13): p. 6002-6..
[27] De, M., et al., Functional characterization of transforming growth factor beta type II receptor mutants in human cancer. Cancer Res, 1998. 58(9): p. 1986-92..
[28] Yasumi, K., et al., Transforming growth factor beta type II receptor (TGF beta RII) mutation in gastric lymphoma without mutator phenotype. Pathol Int, 1998. 48(2): p. 134-7..
[29] Lynch, M.A., et al., Mutational analysis of the transforming growth factor beta receptor type IIgene in human ovarian carcinoma. Cancer Res, 1998. 58(19): p. 4227-32..
[30] Knaus, P.I., et al., A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol, 1996. 16(7): p. 3480-9..
[31] Munoz-Antonia, T., et al., A mutation in the transforming growth factor beta type II receptor gene promoter associated with loss of gene expression. Cancer Res, 1996. 56(21): p. 4831-5..
[32] Hougaard, S., et al., Inactivation of the transforming growth factor beta type II receptor in human small cell lung cancer cell lines. Br J Cancer, 1999. 79(7-8): p. 1005-11..
[33] Park, C., et al., Effects of transforming growth factor beta (TGF-beta) receptor on lung carcinogenesis. Lung Cancer, 2002. 38(2): p. 143-7..
[34] Tani, M., et al., Infrequent mutations of the transforming growth factor beta-type II receptor gene at chromosome 3p22 in human lung cancers with chromosome 3p deletions. Carcinogenesis, 1997. 18(5): p. 1119-21..
[35] Kim, W.S., et al., Microsatellite instability(MSI) in non-small cell lung cancer(NSCLC) is highly associated with transforming growth factor-beta type II receptor(TGF-beta RII) frameshift mutation. Anticancer Res, 2000. 20(3A): p. 1499-502..
[36] Zhang, H.T., et al., Defective expression of transforming growth factor beta receptor type II is associated with CpG methylated promoter in primary non-small cell lung cancer. Clin Cancer Res, 2004. 10(7): p. 2359-67..
[37] Osada, H., et al., Heterogeneous transforming growth factor (TGF)-beta unresponsiveness and loss of TGF-beta receptor type II expression caused by histone deacetylation in lung cancer cell lines. Cancer Res, 2001. 61(22): p. 8331-9..
[38]程慧敏, et al.,非小细胞肺癌TGF-β1、TRFII及Smad2的表达及其临床病理学意义.徐州医学院学报, 2004. 24(4): p. 334-338..
[39]申景岭, et al., TGF-β/Smads在肺癌中的表达研究.遗传学报, 2003. 30(7): p. 681-686..
[40] Bakin, A.V., et al., Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem, 2000. 275(47): p. 36803-10..
[41] Hocevar, B.A., T.L. Brown, and P.H. Howe, TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. Embo J, 1999. 18(5): p. 1345-56..
[42] Miyaki, M., et al., Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene, 1999. 18(20): p. 3098-103..
[43] Chapekar, M.S., A.C. Huggett, and S.S. Thorgeirsson, Growth modulatory effects of aliver-derived growth inhibitor, transforming growth factor beta 1, and recombinant tumor necrosis factor alpha, in normal and neoplastic cells. Exp Cell Res, 1989. 185(1): p. 247-57..
[44] Samouelian, V., et al., Chemosensitivity and radiosensitivity profiles of four new human epithelial ovarian cancer cell lines exhibiting genetic alterations in BRCA2, TGFbeta-RII, KRAS2, TP53 and/or CDNK2A. Cancer Chemother Pharmacol, 2004. 54(6): p. 497-504..
[45] GABRIEL SB, SCHAFFNER SF, NGUYEN H, et al. The structure of haplotype blocks in the human genome. Science. 2002;296:2225-29.
[46] STEPHENS M, DONNELLY P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003;73:1162-69.
[47] SCHAID DJ, ROWLAND CM, TINES DE, JACOBSON RM, POLAND GA. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet. 2002;70:425-34.
[48] GRANT SF, BALDASSANO RN, HAKONARSON H. Classification of genetic profiles of Crohn's disease: a focus on the ATG16L1 gene. Expert Rev Mol Diagn. 2008;8:199-207.
[49] LERCHER MJ, HURST LD. Human SNP variability and mutation rate are higher in regions of high recombination. Trends Genet. 2002;18:337-40.
[50] Thatcher, N., M. Ranson, S.M. Lee, et al. Chemotherapy in non-small cell lung cancer. Ann Oncol, 1995, 6 Suppl 1: 83-94;discussion 94-5..
[51] Tong, X., R. Drapkin, D. Reinberg, et al. The 62- and 80-kDa subunits of transcription factor IIH mediate the interaction with Epstein-Barr virus nuclear protein 2. Proc Natl Acad Sci U S A, 1995, 92(8): 3259-63..
[52] Carlson, C.S., M.A. Eberle, L. Kruglyak, et al. Mapping complex disease loci in whole-genome association studies. Nature, 2004, 429(6990): 446-52..
[53] Frazer, K.A., D.G. Ballinger, D.R. Cox, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature, 2007, 449(7164): 851-61..
[54] 1768027.
[55] WANG JC, SU CC, XU JB, et al. Novel microdeletion in the transforming growth factor beta type II receptor gene is associated with giant and large cell variants of nonsmall cell lung carcinoma. Genes Chromosomes Cancer. 2007;46:192-201.
[56] CHEN Y, YU G, YU D, ZHU M. PKCalpha-induced drug resistance in pancreatic cancer cells is associated with transforming growth factor-beta1. J Exp Clin Cancer Res. 2010;29:104.
[57] SIMPSON BJ, LANGDON SP, RABIASZ GJ, et al. Estrogen regulation of transforming growth factor-alpha in ovarian cancer. J Steroid Biochem Mol Biol. 1998;64:137-45.
[58] BOGUSH TA, DUDKO EA, BEME AA, et al. Estrogen receptors, antiestrogens, and non-small cell lung cancer. Biochemistry (Mosc). 2010;75:1421-27.
[59] Fu YX. Estimating effective population size or mutation rate using the frequencies of mutations of various classes in a sample of DNA sequences. Genetics, 1994, 138 (4):1375-1386..
[60] SCHWARTZ JT. Methodologic differences and measurement of cup-disc ratio: an epidemiologic assessment. Arch Ophthalmol. 1976;94:1101-05.
[61] DUAN R, PAK C, JIN P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124-31.
[62] DUAN R, PAK C, JIN P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124-31.
[63] DUAN R, PAK C, JIN P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124-31.
[64] MISHRA PJ, MISHRA PJ, BANERJEE D, BERTINO JR. MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: Introducing microRNA pharmacogenomics. Cell Cycle. 2008;7:853-58.
[65] DUAN R, PAK C, JIN P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124-31.
[66] DUAN R, PAK C, JIN P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124-31.
[67] ABIDIN MR, TOWLER MA, NOCHIMSON GD, RODEHEAVER GT, THACKER JG, EDLICH RF. A new quantitative measurement for surgical needle ductility. Ann Emerg Med. 1989;18:64-68.
[68] XU T, ZHU Y, WEI QK, et al. A functional polymorphism in the miR-146a gene is associated with the risk for hepatocellular carcinoma. Carcinogenesis. 2008;29:2126-31.
[69] SETHUPATHY P, BOREL C, GAGNEBIN M, et al. Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3' untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet. 2007;81:405-13.
[70] CHIN LJ, RATNER E, LENG S, et al. A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk. Cancer Res. 2008;68:8535-40.
[71] MISHRA PJ, HUMENIUK R, MISHRA PJ, LONGO-SORBELLO GS, BANERJEE D, BERTINO JR. A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci U S A. 2007;104:13513-18.
[1]. Sun, X., et al., Polymorphisms in XRCC1 and XPG and response to platinum-based chemotherapy in advanced non-small cell lung cancer patients. Lung Cancer, 2009. 65(2): p. 230-6.
[2]. Kalikaki, A., et al., DNA repair gene polymorphisms predict favorable clinical outcome in advanced non-small-cell lung cancer. Clin Lung Cancer, 2009. 10(2): p. 118-23.
[3]. Zhou, W., et al., Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res, 2004. 10(15): p. 4939-43.
[4]. Su, D., et al., Genetic polymorphisms and treatment response in advanced non-small cell lung cancer. Lung Cancer, 2007. 56(2): p. 281-8.
[5]. Okuda, K., et al., Excision Repair Cross Complementation Group 1 Polymorphisms Predict Overall Survival after Platinum-Based Chemotherapy for Completely Resected Non-Small-Cell Lung Cancer. J Surg Res, 2009.
[6]. Li, F., et al., Association Between Polymorphisms of ERCC1 and XPD and Clinical Response to Platinum-Based Chemotherapy in Advanced Non-Small Cell Lung Cancer. Am J Clin Oncol, 2010.
[7]. Suk, R., et al., Polymorphisms in ERCC1 and grade 3 or 4 toxicity in non-small cell lung cancer patients. Clin Cancer Res, 2005. 11(4): p. 1534-8.
[8]. Gurubhagavatula, S., et al., XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J Clin Oncol, 2004. 22(13): p. 2594-601.
[9]. Yuan, P., et al., [Polymorphisms in nucleotide excision repair genes XPC and XPD and clinical responses to platinum-based chemotherapy in advanced non-small cell lung cancer]. Zhonghua Yi Xue Za Zhi, 2005. 85(14): p. 972-5.
[10]. Yuan, P., et al., [Correlation of genetic polymorphisms in nucleotide excision repair system to sensitivity of advanced non-small cell lung cancer patients to platinum-based chemotherapy]. Ai Zheng, 2005. 24(12): p. 1510-3.
[11]. Giachino, D.F., et al., Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer. Clin Cancer Res, 2007. 13(10): p. 2876-81.
[12]. Petty, W.J., et al., A pharmacogenomic study of docetaxel and gemcitabine for the initial treatment of advanced non-small cell lung cancer. J Thorac Oncol, 2007. 2(3): p. 197-202.
[13]. Yao, C.Y., et al., Lack of influence of XRCC1 and XPD gene polymorphisms on outcome of platinum-based chemotherapy for advanced non small cell lung cancers. Asian Pac J Cancer Prev, 2009. 10(5): p. 859-64.
[14]. Wu, W., et al., Association of XPD polymorphisms with severe toxicity in non-small cell lung cancer patients in a Chinese population. Clin Cancer Res, 2009. 15(11): p. 3889-95.
[15]. Yuan, P., et al., [Correlation of genetic polymorphisms in nucleotide excision repair system to sensitivity of advanced non-small cell lung cancer patients to platinum-based chemotherapy]. Ai Zheng, 2005. 24(12): p. 1510-3.
[16]. Takenaka, T., et al., Effects of excision repair cross-complementation group 1 (ERCC1) single nucleotide polymorphisms on the prognosis of non-small cell lung cancer patients. Lung Cancer, 2010. 67(1): p. 101-7.
[17]. Yuan, P., et al., [XRCC1 and XPD genetic polymorphisms predict clinical responses to platinum-based chemotherapy in advanced non-small cell lung cancer]. Zhonghua Zhong Liu Za Zhi, 2006. 28(3): p. 196-9.
[18]. Sun, X., et al., Polymorphisms in XRCC1 and XPG and response to platinum-based chemotherapy in advanced non-small cell lung cancer patients. Lung Cancer, 2009. 65(2): p. 230-6.
[19]. Feng, J., et al., XPA A23G polymorphism is associated with the elevated response to platinum-based chemotherapy in advanced non-small cell lung cancer. Acta Biochim Biophys Sin (Shanghai), 2009. 41(5): p. 429-35.
[20]. Giachino, D.F., et al., Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer. Clin Cancer Res, 2007. 13(10): p. 2876-81.
[21]. Cheng, H., et al., Polymorphisms in hMSH2 and hMLH1 and response to platinum-based chemotherapy in advanced non-small-cell lung cancer patients. Acta Biochim Biophys Sin (Shanghai), 2010. 42(5): p. 311-7.
[22]. Kim, H.T., et al., Effect of BRCA1 haplotype on survival of non-small-cell lung cancer patients treated with platinum-based chemotherapy. J Clin Oncol, 2008. 26(36): p. 5972-9.
[23]. Sun, N., et al., MRP2 and GSTP1 polymorphisms and chemotherapy response in advanced non-small cell lung cancer. Cancer Chemother Pharmacol, 2010. 65(3): p. 437-46.
[24]. Lu, C., et al., Association between glutathione S-transferase pi polymorphisms and survival in patients with advanced nonsmall cell lung carcinoma. Cancer, 2006. 106(2): p. 441-7.
[25]. Booton, R., et al., Glutathione-S-transferase P1 isoenzyme polymorphisms, platinum-based chemotherapy, and non-small cell lung cancer. J Thorac Oncol, 2006. 1(7): p. 679-83.
[26]. Gautschi, O., et al., Cyclin D1 (CCND1) A870G gene polymorphism modulates smoking-induced lung cancer risk and response to platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients. Lung Cancer, 2006. 51(3): p. 303-11.
[27]. Yuan, P., et al., [Association of the responsiveness of advanced non-small cell lung cancer toplatinum-based chemotherapy with p53 and p73 polymorphisms]. Zhonghua Zhong Liu Za Zhi, 2006. 28(2): p. 107-10.
[28]. Feng, J.F., et al., Polymorphisms of the ribonucleotide reductase M1 gene and sensitivity to platin-based chemotherapy in non-small cell lung cancer. Lung Cancer, 2009. 66(3): p. 344-9.
1. Barbujani, G., et al., An apportionment of human DNA diversity. Proc Natl Acad Sci U S A, 1997. 94(9): p. 4516-9.
2. Wang, D.G., et al., Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science, 1998. 280(5366): p. 1077-82.
3. Li, W.H. and L.A. Sadler, Low nucleotide diversity in man. Genetics, 1991. 129(2): p. 513-23.
4. Nickerson, D.A., et al., DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet, 1998. 19(3): p. 233-40.
5. Derynck, R., R.J. Akhurst, and A. Balmain, TGF-beta signaling in tumor suppression and cancer progression. Nat Genet, 2001. 29(2): p. 117-29.
6. Derynck, R. and Y.E. Zhang, Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003. 425(6958): p. 577-84.
7. Siegel, P.M. and J. Massague, Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer, 2003. 3(11): p. 807-21.
8. del Re, E., et al., In the absence of type III receptor, the transforming growth factor (TGF)-beta type II-B receptor requires the type I receptor to bind TGF-beta2. J Biol Chem, 2004. 279(21): p. 22765-72.
9. Souchelnytskyi, S., et al., Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem, 1997. 272(44): p. 28107-15.
10. Garrigue-Antar, L., et al., Loss of transforming growth factor-beta type II receptor gene expression in primary human esophageal cancer. Lab Invest, 1996. 75(2): p. 263-72.
11. Tanaka, S., et al., A dominant negative mutation of transforming growth factor-beta receptor type II gene in microsatellite stable oesophageal carcinoma. Br J Cancer, 2000. 82(9): p. 1557-60.
12. Parekh, T.V., et al., Transforming growth factor beta signaling is disabled early in human endometrial carcinogenesis concomitant with loss of growth inhibition. Cancer Res, 2002. 62(10): p. 2778-90.
13.李代蓉and周清华.,肺癌遗传易感性的研究进展.中国肺癌杂志, 2003. 6:: p. 158-162.
14. Mohrenweiser HW and J. M., vairation in DNA repair is a factor in cancer susceptibiltiy. a paradigm for promises and perils of individual and population risk estimation? Mutat Res, 1998. 400(1/2): p. 15-24.
15. Park, K., et al., Genetic changes in the transforming growth factor beta (TGF-beta) type IIreceptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci U S A, 1994. 91(19): p. 8772-6.
16. Markowitz, S., et al., Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science, 1995. 268(5215): p. 1336-8.
17. Capocasale, R.J., et al., Reduced surface expression of transforming growth factor beta receptor type II in mitogen-activated T cells from Sezary patients. Proc Natl Acad Sci U S A, 1995. 92(12): p. 5501-5.
18. Kadin, M.E., et al., Loss of receptors for transforming growth factor beta in human T-cell malignancies. Proc Natl Acad Sci U S A, 1994. 91(13): p. 6002-6.
19. De, M., et al., Functional characterization of transforming growth factor beta type II receptor mutants in human cancer. Cancer Res, 1998. 58(9): p. 1986-92.
20. Yasumi, K., et al., Transforming growth factor beta type II receptor (TGF beta RII) mutation in gastric lymphoma without mutator phenotype. Pathol Int, 1998. 48(2): p. 134-7.
21. Lynch, M.A., et al., Mutational analysis of the transforming growth factor beta receptor type II gene in human ovarian carcinoma. Cancer Res, 1998. 58(19): p. 4227-32.
22. Knaus, P.I., et al., A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol, 1996. 16(7): p. 3480-9.
23. Kim, W.S., et al., Microsatellite instability(MSI) in non-small cell lung cancer(NSCLC) is highly associated with transforming growth factor-beta type II receptor(TGF-beta RII) frameshift mutation. Anticancer Res, 2000. 20(3A): p. 1499-502.
24. Tani, M., et al., Infrequent mutations of the transforming growth factor beta-type II receptor gene at chromosome 3p22 in human lung cancers with chromosome 3p deletions. Carcinogenesis, 1997. 18(5): p. 1119-21.
25. Hougaard, S., et al., Inactivation of the transforming growth factor beta type II receptor in human small cell lung cancer cell lines. Br J Cancer, 1999. 79(7-8): p. 1005-11.
26. Munoz-Antonia, T., et al., A mutation in the transforming growth factor beta type II receptor gene promoter associated with loss of gene expression. Cancer Res, 1996. 56(21): p. 4831-5.
27. Park, C., et al., Effects of transforming growth factor beta (TGF-beta) receptor on lung carcinogenesis. Lung Cancer, 2002. 38(2): p. 143-7.
28. Zhang, H.T., et al., Defective expression of transforming growth factor beta receptor type II is associated with CpG methylated promoter in primary non-small cell lung cancer. Clin Cancer Res, 2004. 10(7): p. 2359-67.
29. Osada, H., et al., Heterogeneous transforming growth factor (TGF)-beta unresponsiveness and loss of TGF-beta receptor type II expression caused by histone deacetylation in lung cancer cell lines. Cancer Res, 2001. 61(22): p. 8331-9.
30.程慧敏, et al.,非小细胞肺癌TGF-β1、TRFII及Smad2的表达及其临床病理学意义.徐州医学院学报, 2004. 24(4): p. 334-338.
31.申景岭, et al., TGF-β/Smads在肺癌中的表达研究.遗传学报, 2003. 30(7): p. 681-686.
32. Bakin, A.V., et al., Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem, 2000. 275(47): p. 36803-10.
33. Hocevar, B.A., T.L. Brown, and P.H. Howe, TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. Embo J, 1999. 18(5): p. 1345-56.
34. Miyaki, M., et al., Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene, 1999. 18(20): p. 3098-103.
35. Maione, P., et al., Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC. Oncologist, 2006. 11(3): p. 274-84.
36. de las Penas, R., et al., Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann Oncol, 2006. 17(4): p. 668-75.
37. Giachino, D.F., et al., Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer. Clin Cancer Res, 2007. 13(10): p. 2876-81.
38. Rosell, R., et al., Influence of genetic markers on survival in non-small cell lung cancer. Drugs Today (Barc), 2003. 39(10): p. 775-86.
39. Camps, C., et al., Assessment of nucleotide excision repair XPD polymorphisms in the peripheral blood of gemcitabine/cisplatin-treated advanced non-small-cell lung cancer patients. Clin Lung Cancer, 2003. 4(4): p. 237-41.
40. Simon, G.R., R. Ismail-Khan, and G. Bepler, Nuclear excision repair-based personalized therapy for non-small cell lung cancer: from hypothesis to reality. Int J Biochem Cell Biol, 2007. 39(7-8): p. 1318-28.
41. Bear, W.L. and R.W. Teel, Effects of citrus phytochemicals on liver and lung cytochrome P450 activity and on the in vitro metabolism of the tobacco-specific nitrosamine NNK. Anticancer Res, 2000. 20(5A): p. 3323-9.
42. Hu, X., et al., Mechanism of differential catalytic efficiency of two polymorphic forms ofhuman glutathione S-transferase P1-1 in the glutathione conjugation of carcinogenic diol epoxide of chrysene. Arch Biochem Biophys, 1997. 345(1): p. 32-8.
43. Mechanic, L.E., et al., Common genetic variation in TP53 is associated with lung cancer risk and prognosis in African Americans and somatic mutations in lung tumors. Cancer Epidemiol Biomarkers Prev, 2007. 16(2): p. 214-22.
44. Choi, Y.Y., et al., Comprehensive assessment of P21 polymorphisms and lung cancer risk. J Hum Genet, 2008. 53(1): p. 87-95.
45. Chen, D., et al., Genetic variants in peroxisome proliferator-activated receptor-gamma gene are associated with risk of lung cancer in a Chinese population. Carcinogenesis, 2008. 29(2): p. 342-50.
46. Su, L., et al., Genotypes and haplotypes of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer. Carcinogenesis, 2006. 27(5): p. 1024-9.
47. Sauter, W., et al., Matrix metalloproteinase 1 (MMP1) is associated with early-onset lung cancer. Cancer Epidemiol Biomarkers Prev, 2008. 17(5): p. 1127-35.
48. Lee, W.K., et al., Polymorphisms in the Caspase7 gene and the risk of lung cancer. Lung Cancer, 2009. 65(1): p. 19-24.
49. Jang, J.S., et al., Identification of polymorphisms in the Caspase-3 gene and their association with lung cancer risk. Mol Carcinog, 2008. 47(5): p. 383-90.
50. Suzuki, A., et al., Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death. Oncogene, 2000. 19(10): p. 1346-53.
51. Yin, J., et al., HapMap-based study of the DNA repair gene ERCC2 and lung cancer susceptibility in a Chinese population. Carcinogenesis, 2009. 30(7): p. 1181-5.
52. Yin, J., et al., A haplotype encompassing the variant allele of DNA repair gene polymorphism ERCC2/XPD Lys751Gln but not the variant allele of Asp312Asn is associated with risk of lung cancer in a northeastern Chinese population. Cancer Genet Cytogenet, 2007. 175(1): p. 47-51.
53. Kang, H.G., et al., Polymorphisms in TGF-beta1 gene and the risk of lung cancer. Lung Cancer, 2006. 52(1): p. 1-7.
[2] SIDDIK ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22:7265-79.
[3] Bear, W.L. and R.W. Teel, Effects of citrus phytochemicals on liver and lung cytochrome P450 activity and on the in vitro metabolism of the tobacco-specific nitrosamine NNK. Anticancer Res, 2000. 20(5A): p. 3323-9..
[4] Hu, X., et al., Mechanism of differential catalytic efficiency of two polymorphic forms of human glutathione S-transferase P1-1 in the glutathione conjugation of carcinogenic diol epoxide of chrysene. Arch Biochem Biophys, 1997. 345(1): p. 32-8..
[5] Mechanic, L.E., et al., Common genetic variation in TP53 is associated with lung cancer risk and prognosis in African Americans and somatic mutations in lung tumors. Cancer Epidemiol Biomarkers Prev, 2007. 16(2): p. 214-22..
[6] Choi, Y.Y., et al., Comprehensive assessment of P21 polymorphisms and lung cancer risk. J Hum Genet, 2008. 53(1): p. 87-95..
[7] Chen, D., et al., Genetic variants in peroxisome proliferator-activated receptor-gamma gene are associated with risk of lung cancer in a Chinese population. Carcinogenesis, 2008. 29(2): p. 342-50..
[8] Su, L., et al., Genotypes and haplotypes of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer. Carcinogenesis, 2006. 27(5): p. 1024-9..
[9] Sauter, W., et al., Matrix metalloproteinase 1 (MMP1) is associated with early-onset lung cancer. Cancer Epidemiol Biomarkers Prev, 2008. 17(5): p. 1127-35..
[10] Lee, W.K., et al., Polymorphisms in the Caspase7 gene and the risk of lung cancer. Lung Cancer, 2009. 65(1): p. 19-24..
[11] Jang, J.S., et al., Identification of polymorphisms in the Caspase-3 gene and their association with lung cancer risk. Mol Carcinog, 2008. 47(5): p. 383-90..
[12] Suzuki, A., et al., Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death. Oncogene, 2000. 19(10): p. 1346-53..
[13] Yin, J., et al., HapMap-based study of the DNA repair gene ERCC2 and lung cancer susceptibility in a Chinese population. Carcinogenesis, 2009. 30(7): p. 1181-5..
[14] Yin, J., et al., A haplotype encompassing the variant allele of DNA repair gene polymorphism ERCC2/XPD Lys751Gln but not the variant allele of Asp312Asn is associated with risk of lung cancer in a northeastern Chinese population. Cancer Genet Cytogenet, 2007. 175(1): p. 47-51..
[15] Kang, H.G., et al., Polymorphisms in TGF-beta1 gene and the risk of lung cancer. Lung Cancer, 2006. 52(1): p. 1-7..
[16] GALLIHER AJ, NEIL JR, SCHIEMANN WP. Role of transforming growth factor-beta in cancer progression. Future Oncol. 2006;2:743-63.
[17] MEULMEESTER E, TEN DP. The dynamic roles of TGF-beta in cancer. J Pathol. 2011;223:205-18.
[18] Derynck, R., R.J. Akhurst, and A. Balmain, TGF-beta signaling in tumor suppression and cancer progression. Nat Genet, 2001. 29(2): p. 117-29..
[19] Derynck, R. and Y.E. Zhang, Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003. 425(6958): p. 577-84..
[20] Siegel, P.M. and J. Massague, Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer, 2003. 3(11): p. 807-21..
[21] del Re, E., et al., In the absence of type III receptor, the transforming growth factor (TGF)-beta type II-B receptor requires the type I receptor to bind TGF-beta2. J Biol Chem, 2004. 279(21): p. 22765-72..
[22] Souchelnytskyi, S., et al., Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem, 1997. 272(44): p. 28107-15.
[23] Park, K., et al., Genetic changes in the transforming growth factor beta (TGF-beta) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci U S A, 1994. 91(19): p. 8772-6..
[24] Markowitz, S., et al., Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science, 1995. 268(5215): p. 1336-8..
[25] Capocasale, R.J., et al., Reduced surface expression of transforming growth factor beta receptor type II in mitogen-activated T cells from Sezary patients. Proc Natl Acad Sci U S A, 1995. 92(12): p. 5501-5..
[26] Kadin, M.E., et al., Loss of receptors for transforming growth factor beta in human T-cell malignancies. Proc Natl Acad Sci U S A, 1994. 91(13): p. 6002-6..
[27] De, M., et al., Functional characterization of transforming growth factor beta type II receptor mutants in human cancer. Cancer Res, 1998. 58(9): p. 1986-92..
[28] Yasumi, K., et al., Transforming growth factor beta type II receptor (TGF beta RII) mutation in gastric lymphoma without mutator phenotype. Pathol Int, 1998. 48(2): p. 134-7..
[29] Lynch, M.A., et al., Mutational analysis of the transforming growth factor beta receptor type IIgene in human ovarian carcinoma. Cancer Res, 1998. 58(19): p. 4227-32..
[30] Knaus, P.I., et al., A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol, 1996. 16(7): p. 3480-9..
[31] Munoz-Antonia, T., et al., A mutation in the transforming growth factor beta type II receptor gene promoter associated with loss of gene expression. Cancer Res, 1996. 56(21): p. 4831-5..
[32] Hougaard, S., et al., Inactivation of the transforming growth factor beta type II receptor in human small cell lung cancer cell lines. Br J Cancer, 1999. 79(7-8): p. 1005-11..
[33] Park, C., et al., Effects of transforming growth factor beta (TGF-beta) receptor on lung carcinogenesis. Lung Cancer, 2002. 38(2): p. 143-7..
[34] Tani, M., et al., Infrequent mutations of the transforming growth factor beta-type II receptor gene at chromosome 3p22 in human lung cancers with chromosome 3p deletions. Carcinogenesis, 1997. 18(5): p. 1119-21..
[35] Kim, W.S., et al., Microsatellite instability(MSI) in non-small cell lung cancer(NSCLC) is highly associated with transforming growth factor-beta type II receptor(TGF-beta RII) frameshift mutation. Anticancer Res, 2000. 20(3A): p. 1499-502..
[36] Zhang, H.T., et al., Defective expression of transforming growth factor beta receptor type II is associated with CpG methylated promoter in primary non-small cell lung cancer. Clin Cancer Res, 2004. 10(7): p. 2359-67..
[37] Osada, H., et al., Heterogeneous transforming growth factor (TGF)-beta unresponsiveness and loss of TGF-beta receptor type II expression caused by histone deacetylation in lung cancer cell lines. Cancer Res, 2001. 61(22): p. 8331-9..
[38]程慧敏, et al.,非小细胞肺癌TGF-β1、TRFII及Smad2的表达及其临床病理学意义.徐州医学院学报, 2004. 24(4): p. 334-338..
[39]申景岭, et al., TGF-β/Smads在肺癌中的表达研究.遗传学报, 2003. 30(7): p. 681-686..
[40] Bakin, A.V., et al., Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem, 2000. 275(47): p. 36803-10..
[41] Hocevar, B.A., T.L. Brown, and P.H. Howe, TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. Embo J, 1999. 18(5): p. 1345-56..
[42] Miyaki, M., et al., Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene, 1999. 18(20): p. 3098-103..
[43] Chapekar, M.S., A.C. Huggett, and S.S. Thorgeirsson, Growth modulatory effects of aliver-derived growth inhibitor, transforming growth factor beta 1, and recombinant tumor necrosis factor alpha, in normal and neoplastic cells. Exp Cell Res, 1989. 185(1): p. 247-57..
[44] Samouelian, V., et al., Chemosensitivity and radiosensitivity profiles of four new human epithelial ovarian cancer cell lines exhibiting genetic alterations in BRCA2, TGFbeta-RII, KRAS2, TP53 and/or CDNK2A. Cancer Chemother Pharmacol, 2004. 54(6): p. 497-504..
[45] GABRIEL SB, SCHAFFNER SF, NGUYEN H, et al. The structure of haplotype blocks in the human genome. Science. 2002;296:2225-29.
[46] STEPHENS M, DONNELLY P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003;73:1162-69.
[47] SCHAID DJ, ROWLAND CM, TINES DE, JACOBSON RM, POLAND GA. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet. 2002;70:425-34.
[48] GRANT SF, BALDASSANO RN, HAKONARSON H. Classification of genetic profiles of Crohn's disease: a focus on the ATG16L1 gene. Expert Rev Mol Diagn. 2008;8:199-207.
[49] LERCHER MJ, HURST LD. Human SNP variability and mutation rate are higher in regions of high recombination. Trends Genet. 2002;18:337-40.
[50] Thatcher, N., M. Ranson, S.M. Lee, et al. Chemotherapy in non-small cell lung cancer. Ann Oncol, 1995, 6 Suppl 1: 83-94;discussion 94-5..
[51] Tong, X., R. Drapkin, D. Reinberg, et al. The 62- and 80-kDa subunits of transcription factor IIH mediate the interaction with Epstein-Barr virus nuclear protein 2. Proc Natl Acad Sci U S A, 1995, 92(8): 3259-63..
[52] Carlson, C.S., M.A. Eberle, L. Kruglyak, et al. Mapping complex disease loci in whole-genome association studies. Nature, 2004, 429(6990): 446-52..
[53] Frazer, K.A., D.G. Ballinger, D.R. Cox, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature, 2007, 449(7164): 851-61..
[54] 1768027.
[55] WANG JC, SU CC, XU JB, et al. Novel microdeletion in the transforming growth factor beta type II receptor gene is associated with giant and large cell variants of nonsmall cell lung carcinoma. Genes Chromosomes Cancer. 2007;46:192-201.
[56] CHEN Y, YU G, YU D, ZHU M. PKCalpha-induced drug resistance in pancreatic cancer cells is associated with transforming growth factor-beta1. J Exp Clin Cancer Res. 2010;29:104.
[57] SIMPSON BJ, LANGDON SP, RABIASZ GJ, et al. Estrogen regulation of transforming growth factor-alpha in ovarian cancer. J Steroid Biochem Mol Biol. 1998;64:137-45.
[58] BOGUSH TA, DUDKO EA, BEME AA, et al. Estrogen receptors, antiestrogens, and non-small cell lung cancer. Biochemistry (Mosc). 2010;75:1421-27.
[59] Fu YX. Estimating effective population size or mutation rate using the frequencies of mutations of various classes in a sample of DNA sequences. Genetics, 1994, 138 (4):1375-1386..
[60] SCHWARTZ JT. Methodologic differences and measurement of cup-disc ratio: an epidemiologic assessment. Arch Ophthalmol. 1976;94:1101-05.
[61] DUAN R, PAK C, JIN P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124-31.
[62] DUAN R, PAK C, JIN P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124-31.
[63] DUAN R, PAK C, JIN P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124-31.
[64] MISHRA PJ, MISHRA PJ, BANERJEE D, BERTINO JR. MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: Introducing microRNA pharmacogenomics. Cell Cycle. 2008;7:853-58.
[65] DUAN R, PAK C, JIN P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124-31.
[66] DUAN R, PAK C, JIN P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124-31.
[67] ABIDIN MR, TOWLER MA, NOCHIMSON GD, RODEHEAVER GT, THACKER JG, EDLICH RF. A new quantitative measurement for surgical needle ductility. Ann Emerg Med. 1989;18:64-68.
[68] XU T, ZHU Y, WEI QK, et al. A functional polymorphism in the miR-146a gene is associated with the risk for hepatocellular carcinoma. Carcinogenesis. 2008;29:2126-31.
[69] SETHUPATHY P, BOREL C, GAGNEBIN M, et al. Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3' untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet. 2007;81:405-13.
[70] CHIN LJ, RATNER E, LENG S, et al. A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk. Cancer Res. 2008;68:8535-40.
[71] MISHRA PJ, HUMENIUK R, MISHRA PJ, LONGO-SORBELLO GS, BANERJEE D, BERTINO JR. A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci U S A. 2007;104:13513-18.
[1]. Sun, X., et al., Polymorphisms in XRCC1 and XPG and response to platinum-based chemotherapy in advanced non-small cell lung cancer patients. Lung Cancer, 2009. 65(2): p. 230-6.
[2]. Kalikaki, A., et al., DNA repair gene polymorphisms predict favorable clinical outcome in advanced non-small-cell lung cancer. Clin Lung Cancer, 2009. 10(2): p. 118-23.
[3]. Zhou, W., et al., Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res, 2004. 10(15): p. 4939-43.
[4]. Su, D., et al., Genetic polymorphisms and treatment response in advanced non-small cell lung cancer. Lung Cancer, 2007. 56(2): p. 281-8.
[5]. Okuda, K., et al., Excision Repair Cross Complementation Group 1 Polymorphisms Predict Overall Survival after Platinum-Based Chemotherapy for Completely Resected Non-Small-Cell Lung Cancer. J Surg Res, 2009.
[6]. Li, F., et al., Association Between Polymorphisms of ERCC1 and XPD and Clinical Response to Platinum-Based Chemotherapy in Advanced Non-Small Cell Lung Cancer. Am J Clin Oncol, 2010.
[7]. Suk, R., et al., Polymorphisms in ERCC1 and grade 3 or 4 toxicity in non-small cell lung cancer patients. Clin Cancer Res, 2005. 11(4): p. 1534-8.
[8]. Gurubhagavatula, S., et al., XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J Clin Oncol, 2004. 22(13): p. 2594-601.
[9]. Yuan, P., et al., [Polymorphisms in nucleotide excision repair genes XPC and XPD and clinical responses to platinum-based chemotherapy in advanced non-small cell lung cancer]. Zhonghua Yi Xue Za Zhi, 2005. 85(14): p. 972-5.
[10]. Yuan, P., et al., [Correlation of genetic polymorphisms in nucleotide excision repair system to sensitivity of advanced non-small cell lung cancer patients to platinum-based chemotherapy]. Ai Zheng, 2005. 24(12): p. 1510-3.
[11]. Giachino, D.F., et al., Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer. Clin Cancer Res, 2007. 13(10): p. 2876-81.
[12]. Petty, W.J., et al., A pharmacogenomic study of docetaxel and gemcitabine for the initial treatment of advanced non-small cell lung cancer. J Thorac Oncol, 2007. 2(3): p. 197-202.
[13]. Yao, C.Y., et al., Lack of influence of XRCC1 and XPD gene polymorphisms on outcome of platinum-based chemotherapy for advanced non small cell lung cancers. Asian Pac J Cancer Prev, 2009. 10(5): p. 859-64.
[14]. Wu, W., et al., Association of XPD polymorphisms with severe toxicity in non-small cell lung cancer patients in a Chinese population. Clin Cancer Res, 2009. 15(11): p. 3889-95.
[15]. Yuan, P., et al., [Correlation of genetic polymorphisms in nucleotide excision repair system to sensitivity of advanced non-small cell lung cancer patients to platinum-based chemotherapy]. Ai Zheng, 2005. 24(12): p. 1510-3.
[16]. Takenaka, T., et al., Effects of excision repair cross-complementation group 1 (ERCC1) single nucleotide polymorphisms on the prognosis of non-small cell lung cancer patients. Lung Cancer, 2010. 67(1): p. 101-7.
[17]. Yuan, P., et al., [XRCC1 and XPD genetic polymorphisms predict clinical responses to platinum-based chemotherapy in advanced non-small cell lung cancer]. Zhonghua Zhong Liu Za Zhi, 2006. 28(3): p. 196-9.
[18]. Sun, X., et al., Polymorphisms in XRCC1 and XPG and response to platinum-based chemotherapy in advanced non-small cell lung cancer patients. Lung Cancer, 2009. 65(2): p. 230-6.
[19]. Feng, J., et al., XPA A23G polymorphism is associated with the elevated response to platinum-based chemotherapy in advanced non-small cell lung cancer. Acta Biochim Biophys Sin (Shanghai), 2009. 41(5): p. 429-35.
[20]. Giachino, D.F., et al., Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer. Clin Cancer Res, 2007. 13(10): p. 2876-81.
[21]. Cheng, H., et al., Polymorphisms in hMSH2 and hMLH1 and response to platinum-based chemotherapy in advanced non-small-cell lung cancer patients. Acta Biochim Biophys Sin (Shanghai), 2010. 42(5): p. 311-7.
[22]. Kim, H.T., et al., Effect of BRCA1 haplotype on survival of non-small-cell lung cancer patients treated with platinum-based chemotherapy. J Clin Oncol, 2008. 26(36): p. 5972-9.
[23]. Sun, N., et al., MRP2 and GSTP1 polymorphisms and chemotherapy response in advanced non-small cell lung cancer. Cancer Chemother Pharmacol, 2010. 65(3): p. 437-46.
[24]. Lu, C., et al., Association between glutathione S-transferase pi polymorphisms and survival in patients with advanced nonsmall cell lung carcinoma. Cancer, 2006. 106(2): p. 441-7.
[25]. Booton, R., et al., Glutathione-S-transferase P1 isoenzyme polymorphisms, platinum-based chemotherapy, and non-small cell lung cancer. J Thorac Oncol, 2006. 1(7): p. 679-83.
[26]. Gautschi, O., et al., Cyclin D1 (CCND1) A870G gene polymorphism modulates smoking-induced lung cancer risk and response to platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients. Lung Cancer, 2006. 51(3): p. 303-11.
[27]. Yuan, P., et al., [Association of the responsiveness of advanced non-small cell lung cancer toplatinum-based chemotherapy with p53 and p73 polymorphisms]. Zhonghua Zhong Liu Za Zhi, 2006. 28(2): p. 107-10.
[28]. Feng, J.F., et al., Polymorphisms of the ribonucleotide reductase M1 gene and sensitivity to platin-based chemotherapy in non-small cell lung cancer. Lung Cancer, 2009. 66(3): p. 344-9.
1. Barbujani, G., et al., An apportionment of human DNA diversity. Proc Natl Acad Sci U S A, 1997. 94(9): p. 4516-9.
2. Wang, D.G., et al., Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science, 1998. 280(5366): p. 1077-82.
3. Li, W.H. and L.A. Sadler, Low nucleotide diversity in man. Genetics, 1991. 129(2): p. 513-23.
4. Nickerson, D.A., et al., DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet, 1998. 19(3): p. 233-40.
5. Derynck, R., R.J. Akhurst, and A. Balmain, TGF-beta signaling in tumor suppression and cancer progression. Nat Genet, 2001. 29(2): p. 117-29.
6. Derynck, R. and Y.E. Zhang, Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003. 425(6958): p. 577-84.
7. Siegel, P.M. and J. Massague, Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer, 2003. 3(11): p. 807-21.
8. del Re, E., et al., In the absence of type III receptor, the transforming growth factor (TGF)-beta type II-B receptor requires the type I receptor to bind TGF-beta2. J Biol Chem, 2004. 279(21): p. 22765-72.
9. Souchelnytskyi, S., et al., Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem, 1997. 272(44): p. 28107-15.
10. Garrigue-Antar, L., et al., Loss of transforming growth factor-beta type II receptor gene expression in primary human esophageal cancer. Lab Invest, 1996. 75(2): p. 263-72.
11. Tanaka, S., et al., A dominant negative mutation of transforming growth factor-beta receptor type II gene in microsatellite stable oesophageal carcinoma. Br J Cancer, 2000. 82(9): p. 1557-60.
12. Parekh, T.V., et al., Transforming growth factor beta signaling is disabled early in human endometrial carcinogenesis concomitant with loss of growth inhibition. Cancer Res, 2002. 62(10): p. 2778-90.
13.李代蓉and周清华.,肺癌遗传易感性的研究进展.中国肺癌杂志, 2003. 6:: p. 158-162.
14. Mohrenweiser HW and J. M., vairation in DNA repair is a factor in cancer susceptibiltiy. a paradigm for promises and perils of individual and population risk estimation? Mutat Res, 1998. 400(1/2): p. 15-24.
15. Park, K., et al., Genetic changes in the transforming growth factor beta (TGF-beta) type IIreceptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci U S A, 1994. 91(19): p. 8772-6.
16. Markowitz, S., et al., Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science, 1995. 268(5215): p. 1336-8.
17. Capocasale, R.J., et al., Reduced surface expression of transforming growth factor beta receptor type II in mitogen-activated T cells from Sezary patients. Proc Natl Acad Sci U S A, 1995. 92(12): p. 5501-5.
18. Kadin, M.E., et al., Loss of receptors for transforming growth factor beta in human T-cell malignancies. Proc Natl Acad Sci U S A, 1994. 91(13): p. 6002-6.
19. De, M., et al., Functional characterization of transforming growth factor beta type II receptor mutants in human cancer. Cancer Res, 1998. 58(9): p. 1986-92.
20. Yasumi, K., et al., Transforming growth factor beta type II receptor (TGF beta RII) mutation in gastric lymphoma without mutator phenotype. Pathol Int, 1998. 48(2): p. 134-7.
21. Lynch, M.A., et al., Mutational analysis of the transforming growth factor beta receptor type II gene in human ovarian carcinoma. Cancer Res, 1998. 58(19): p. 4227-32.
22. Knaus, P.I., et al., A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol, 1996. 16(7): p. 3480-9.
23. Kim, W.S., et al., Microsatellite instability(MSI) in non-small cell lung cancer(NSCLC) is highly associated with transforming growth factor-beta type II receptor(TGF-beta RII) frameshift mutation. Anticancer Res, 2000. 20(3A): p. 1499-502.
24. Tani, M., et al., Infrequent mutations of the transforming growth factor beta-type II receptor gene at chromosome 3p22 in human lung cancers with chromosome 3p deletions. Carcinogenesis, 1997. 18(5): p. 1119-21.
25. Hougaard, S., et al., Inactivation of the transforming growth factor beta type II receptor in human small cell lung cancer cell lines. Br J Cancer, 1999. 79(7-8): p. 1005-11.
26. Munoz-Antonia, T., et al., A mutation in the transforming growth factor beta type II receptor gene promoter associated with loss of gene expression. Cancer Res, 1996. 56(21): p. 4831-5.
27. Park, C., et al., Effects of transforming growth factor beta (TGF-beta) receptor on lung carcinogenesis. Lung Cancer, 2002. 38(2): p. 143-7.
28. Zhang, H.T., et al., Defective expression of transforming growth factor beta receptor type II is associated with CpG methylated promoter in primary non-small cell lung cancer. Clin Cancer Res, 2004. 10(7): p. 2359-67.
29. Osada, H., et al., Heterogeneous transforming growth factor (TGF)-beta unresponsiveness and loss of TGF-beta receptor type II expression caused by histone deacetylation in lung cancer cell lines. Cancer Res, 2001. 61(22): p. 8331-9.
30.程慧敏, et al.,非小细胞肺癌TGF-β1、TRFII及Smad2的表达及其临床病理学意义.徐州医学院学报, 2004. 24(4): p. 334-338.
31.申景岭, et al., TGF-β/Smads在肺癌中的表达研究.遗传学报, 2003. 30(7): p. 681-686.
32. Bakin, A.V., et al., Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem, 2000. 275(47): p. 36803-10.
33. Hocevar, B.A., T.L. Brown, and P.H. Howe, TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. Embo J, 1999. 18(5): p. 1345-56.
34. Miyaki, M., et al., Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene, 1999. 18(20): p. 3098-103.
35. Maione, P., et al., Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC. Oncologist, 2006. 11(3): p. 274-84.
36. de las Penas, R., et al., Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann Oncol, 2006. 17(4): p. 668-75.
37. Giachino, D.F., et al., Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer. Clin Cancer Res, 2007. 13(10): p. 2876-81.
38. Rosell, R., et al., Influence of genetic markers on survival in non-small cell lung cancer. Drugs Today (Barc), 2003. 39(10): p. 775-86.
39. Camps, C., et al., Assessment of nucleotide excision repair XPD polymorphisms in the peripheral blood of gemcitabine/cisplatin-treated advanced non-small-cell lung cancer patients. Clin Lung Cancer, 2003. 4(4): p. 237-41.
40. Simon, G.R., R. Ismail-Khan, and G. Bepler, Nuclear excision repair-based personalized therapy for non-small cell lung cancer: from hypothesis to reality. Int J Biochem Cell Biol, 2007. 39(7-8): p. 1318-28.
41. Bear, W.L. and R.W. Teel, Effects of citrus phytochemicals on liver and lung cytochrome P450 activity and on the in vitro metabolism of the tobacco-specific nitrosamine NNK. Anticancer Res, 2000. 20(5A): p. 3323-9.
42. Hu, X., et al., Mechanism of differential catalytic efficiency of two polymorphic forms ofhuman glutathione S-transferase P1-1 in the glutathione conjugation of carcinogenic diol epoxide of chrysene. Arch Biochem Biophys, 1997. 345(1): p. 32-8.
43. Mechanic, L.E., et al., Common genetic variation in TP53 is associated with lung cancer risk and prognosis in African Americans and somatic mutations in lung tumors. Cancer Epidemiol Biomarkers Prev, 2007. 16(2): p. 214-22.
44. Choi, Y.Y., et al., Comprehensive assessment of P21 polymorphisms and lung cancer risk. J Hum Genet, 2008. 53(1): p. 87-95.
45. Chen, D., et al., Genetic variants in peroxisome proliferator-activated receptor-gamma gene are associated with risk of lung cancer in a Chinese population. Carcinogenesis, 2008. 29(2): p. 342-50.
46. Su, L., et al., Genotypes and haplotypes of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer. Carcinogenesis, 2006. 27(5): p. 1024-9.
47. Sauter, W., et al., Matrix metalloproteinase 1 (MMP1) is associated with early-onset lung cancer. Cancer Epidemiol Biomarkers Prev, 2008. 17(5): p. 1127-35.
48. Lee, W.K., et al., Polymorphisms in the Caspase7 gene and the risk of lung cancer. Lung Cancer, 2009. 65(1): p. 19-24.
49. Jang, J.S., et al., Identification of polymorphisms in the Caspase-3 gene and their association with lung cancer risk. Mol Carcinog, 2008. 47(5): p. 383-90.
50. Suzuki, A., et al., Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death. Oncogene, 2000. 19(10): p. 1346-53.
51. Yin, J., et al., HapMap-based study of the DNA repair gene ERCC2 and lung cancer susceptibility in a Chinese population. Carcinogenesis, 2009. 30(7): p. 1181-5.
52. Yin, J., et al., A haplotype encompassing the variant allele of DNA repair gene polymorphism ERCC2/XPD Lys751Gln but not the variant allele of Asp312Asn is associated with risk of lung cancer in a northeastern Chinese population. Cancer Genet Cytogenet, 2007. 175(1): p. 47-51.
53. Kang, H.G., et al., Polymorphisms in TGF-beta1 gene and the risk of lung cancer. Lung Cancer, 2006. 52(1): p. 1-7.