TGFBR1基因单倍型及其启动子区甲基化情况与非小细胞肺癌关系的研究
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摘要
第一部分TGFBR1基因启动子区甲基化与非小细胞肺癌关系研究
转化生长因子β(TGF-β)介导的信号转导通路的耐受现象经常在包括非小细胞肺癌细胞在内的许多恶性肿瘤细胞中出现。这种现象可能与TGF-β受体1(TGFBR1)的表达下调有关。但是,到目前为止还没有关于TGFBR1基因失活及其启动子区CpG位点的甲基化存在情况与非小细胞肺癌的关系的研究报道。为了研究表观机制是否是非小细胞肺癌中TGFBR1失活的潜在因素之一,我们采用免疫组织化学的方法和DNA甲基化分析的方法,对35例切除术病例的癌组织和相应的癌旁组织进行了研究。我们的研究首次发现,在35例非小细胞肺癌组织中,有11例(31.4%)的TGFBR1表达缺失或减少,这表明TGFBR1表达下调可能会导致非小细胞肺癌的发生和恶化。但是,在TGFBR1启动子区的-362到-142区域,我们并没有发现有异常的DNA甲基化出现。
第二部分TGFBR1基因多态性及其单倍型与非小细胞肺癌易感性关系研究
转化生长因子受体1(TGFBR1)是转化生长因子受体(TGF-βreceptors)家族成员之一,它主要参与TGF-β介导的细胞生长和分化,并且经常在非小细胞肺癌(NSCLC)细胞中失活。目前关于TGFBR1单倍型和非小细胞肺癌易感性的相关性研究还未有报道。我们假设TGFBR1单核苷酸多态位点(SNPs)及其单倍型可能与非小细胞肺癌易感性相关,并对此假设进行了研究。在两组来自不同地区的病例-对照样本中,我们对TGFBR1基因序列上的7个单倍型标签SNP(htSNP)进行了基因分型,其中6个htSNP的基因型检测使用PCR-限制性酶切多态性(PCR-RFLP)的方法,还有一个htSNP使用PCR-单链构象多态性的方法来检测。病例-对照组1的样本来自苏州,包括102例非小细胞肺癌病人和104例对照。病例-对照组2的样本来自无锡,包括131例非小细胞肺癌病人和133例对照。根据这7个htSNP的基因分型数据和连锁不平衡状况我们对单倍型进行了重构。在两个病例对照组中的任何一个htSNP都与非小细胞肺癌易感性不相关。但是,在两个研究组中,一个四位点单倍型,CTGC,在对照组中出现的频率显著高于病人组(两组中P值分别为0.014和0.010)。表明这个单倍型对于降低非小细胞肺癌发病风险有贡献(研究组1:校正OR,0.09;95% CI,0.01-0.61;研究组2:校正OR,0.11;95% CI,0.03-0.39)。本研究首次发现TGFBR1单倍型与非小细胞肺癌易感性相关。
Part 1 Association of TGFBR1 Promoter Methylation Status with Non-small Cell Lung Cancer
Many malignant tumor cells, including non-small cell lung cancer (NSCLC) cells, are frequently resistant to transforming growth factorβ(TGF-β)-mediated signal transduction. This refractory response might be due to reduced/loss expression of the TGF-βreceptor 1 (TGFBR1). However, little was known about connection between inactivation of the TGFBR1 gene and the presence of CpG methylated promoter in NSCLC. To investigate whether, there is an epigenetic mechanism underlying inactivation of TGFBR1 in NSCLC, we performed the immunohistochemical and DNA methylation analyzes of TGFBR1 in tumor and the paired normal tissues from 35 resection specimens. As the first report, the present study demonstrated loss or reduction of TGFBR1 expression in 11 (31.4%) of 35 NSCLC tissues, suggesting that reduced TGFBR1 expression could contribute to the development of malignant phenotype of NSCLC, even if no aberrant DNA methylated site was found at sites -362 to -142 of TGFBR1 promoter region under investigation.
Part 2 Association of TGFBR1 Polymorphisms and Haplotypes with Non-small Cell Lung Cancer
Transforming growth factor beta (TGF-β) receptors, including TGF-βreceptor type 1 (TGFBR1), are centrally involved in TGF-β-mediated cell growth and differentiation and are frequently inactivated in non-small cell lung cancer (NSCLC) cells. The association of TGFBR1 haplotypes with risk for NSCLC has not yet been studied. We tested the hypothesis that single nucleotide polymorphisms (SNPs) and/or TGFBR1 haplotypes are associated with risk of NSCLC. We genotyped six TGFBR1 haplotype tagging SNPs (htSNPs) by PCR-restriction fragment length polymorphism (PCR-RFLP) assays and one htSNP by PCR-single strand conformation polymorphism (PCR-SSCP) assay in two case-control studies. Case-control study 1 included 102 NSCLC patients and 104 controls from Suzhou. Case-control study 2 included 131 patients with NSCLC and 133 controls from Wuxi. Individuals included in two case-control studies were Han Chinese. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium (LD) status of these seven htSNPs. None of the htSNP was associated with NSCLC risk in anyone of two case-control studies. However, a four-marker haplotype CTGC was significantly more common among controls than among cases in two case-control studies (P=0.014 and P=0.010, respectively) indicating that this haplotype is associated with decreased NSCLC risk (adjusted OR, 0.09; 95% CI, 0.01-0.61 and adjusted OR, 0.11; 95% CI, 0.02-0.59, respectively). Combined analysis of both studies shows an association of this four-marker haplotye with decreased NSCLC risk (adjusted OR, 0.11; 95% CI, 0.03-0.39). This is the first evidence of an association between a TGFBR1 haplotype and risk for NSCLC.
转化生长因子β(TGF-β)介导的信号转导通路的耐受现象经常在包括非小细胞肺癌细胞在内的许多恶性肿瘤细胞中出现。这种现象可能与TGF-β受体1(TGFBR1)的表达下调有关。但是,到目前为止还没有关于TGFBR1基因失活及其启动子区CpG位点的甲基化存在情况与非小细胞肺癌的关系的研究报道。为了研究表观机制是否是非小细胞肺癌中TGFBR1失活的潜在因素之一,我们采用免疫组织化学的方法和DNA甲基化分析的方法,对35例切除术病例的癌组织和相应的癌旁组织进行了研究。我们的研究首次发现,在35例非小细胞肺癌组织中,有11例(31.4%)的TGFBR1表达缺失或减少,这表明TGFBR1表达下调可能会导致非小细胞肺癌的发生和恶化。但是,在TGFBR1启动子区的-362到-142区域,我们并没有发现有异常的DNA甲基化出现。
第二部分TGFBR1基因多态性及其单倍型与非小细胞肺癌易感性关系研究
转化生长因子受体1(TGFBR1)是转化生长因子受体(TGF-βreceptors)家族成员之一,它主要参与TGF-β介导的细胞生长和分化,并且经常在非小细胞肺癌(NSCLC)细胞中失活。目前关于TGFBR1单倍型和非小细胞肺癌易感性的相关性研究还未有报道。我们假设TGFBR1单核苷酸多态位点(SNPs)及其单倍型可能与非小细胞肺癌易感性相关,并对此假设进行了研究。在两组来自不同地区的病例-对照样本中,我们对TGFBR1基因序列上的7个单倍型标签SNP(htSNP)进行了基因分型,其中6个htSNP的基因型检测使用PCR-限制性酶切多态性(PCR-RFLP)的方法,还有一个htSNP使用PCR-单链构象多态性的方法来检测。病例-对照组1的样本来自苏州,包括102例非小细胞肺癌病人和104例对照。病例-对照组2的样本来自无锡,包括131例非小细胞肺癌病人和133例对照。根据这7个htSNP的基因分型数据和连锁不平衡状况我们对单倍型进行了重构。在两个病例对照组中的任何一个htSNP都与非小细胞肺癌易感性不相关。但是,在两个研究组中,一个四位点单倍型,CTGC,在对照组中出现的频率显著高于病人组(两组中P值分别为0.014和0.010)。表明这个单倍型对于降低非小细胞肺癌发病风险有贡献(研究组1:校正OR,0.09;95% CI,0.01-0.61;研究组2:校正OR,0.11;95% CI,0.03-0.39)。本研究首次发现TGFBR1单倍型与非小细胞肺癌易感性相关。
Part 1 Association of TGFBR1 Promoter Methylation Status with Non-small Cell Lung Cancer
Many malignant tumor cells, including non-small cell lung cancer (NSCLC) cells, are frequently resistant to transforming growth factorβ(TGF-β)-mediated signal transduction. This refractory response might be due to reduced/loss expression of the TGF-βreceptor 1 (TGFBR1). However, little was known about connection between inactivation of the TGFBR1 gene and the presence of CpG methylated promoter in NSCLC. To investigate whether, there is an epigenetic mechanism underlying inactivation of TGFBR1 in NSCLC, we performed the immunohistochemical and DNA methylation analyzes of TGFBR1 in tumor and the paired normal tissues from 35 resection specimens. As the first report, the present study demonstrated loss or reduction of TGFBR1 expression in 11 (31.4%) of 35 NSCLC tissues, suggesting that reduced TGFBR1 expression could contribute to the development of malignant phenotype of NSCLC, even if no aberrant DNA methylated site was found at sites -362 to -142 of TGFBR1 promoter region under investigation.
Part 2 Association of TGFBR1 Polymorphisms and Haplotypes with Non-small Cell Lung Cancer
Transforming growth factor beta (TGF-β) receptors, including TGF-βreceptor type 1 (TGFBR1), are centrally involved in TGF-β-mediated cell growth and differentiation and are frequently inactivated in non-small cell lung cancer (NSCLC) cells. The association of TGFBR1 haplotypes with risk for NSCLC has not yet been studied. We tested the hypothesis that single nucleotide polymorphisms (SNPs) and/or TGFBR1 haplotypes are associated with risk of NSCLC. We genotyped six TGFBR1 haplotype tagging SNPs (htSNPs) by PCR-restriction fragment length polymorphism (PCR-RFLP) assays and one htSNP by PCR-single strand conformation polymorphism (PCR-SSCP) assay in two case-control studies. Case-control study 1 included 102 NSCLC patients and 104 controls from Suzhou. Case-control study 2 included 131 patients with NSCLC and 133 controls from Wuxi. Individuals included in two case-control studies were Han Chinese. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium (LD) status of these seven htSNPs. None of the htSNP was associated with NSCLC risk in anyone of two case-control studies. However, a four-marker haplotype CTGC was significantly more common among controls than among cases in two case-control studies (P=0.014 and P=0.010, respectively) indicating that this haplotype is associated with decreased NSCLC risk (adjusted OR, 0.09; 95% CI, 0.01-0.61 and adjusted OR, 0.11; 95% CI, 0.02-0.59, respectively). Combined analysis of both studies shows an association of this four-marker haplotye with decreased NSCLC risk (adjusted OR, 0.11; 95% CI, 0.03-0.39). This is the first evidence of an association between a TGFBR1 haplotype and risk for NSCLC.
引文
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8. Wagner M, Kleeff J, Friess H, Buchler MW, Korc M. Enhanced expression of the type II transforming growth factor-beta receptor is associated with decreased survival in human pancreatic cancer. Pancreas 1999; 19: 370-376.
9. Colasante A, Aiello FB, Brunetti M, di Giovine FS. Gene expression of transforming growth factor beta receptors I and II in non-small-cell lung tumors. Cytokine 2003; 24: 182-189.
10. Song B, Margolin S, Skoglund J, et al. TGFBR1(*)6A and Int7G24A variants of transforming growth factor-beta receptor 1 in Swedish familial and sporadic breast cancer. Br J Cancer 2007; 97: 1175-1179.
11. Baxter SW, Choong DY, Eccles DM, Campbell IG. Transforming growth factor beta receptor 1 polyalanine polymorphism and exon 5 mutation analysis in breast and ovarian cancer. Cancer Epidemiol Biomarkers Prev 2002; 11: 211-214.
12. Pasche B, Kolachana P, Nafa K, et al. TbetaR-I(6A) is a candidate tumor susceptibility allele. Cancer Res 1999; 59: 5678-5682.
13. Chen T, de Vries EG, Hollema H, et al. Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma. Int J Cancer 1999; 82: 43-51.
14. Chen T, Jackson C, Costello B, et al. An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder. Int J Cancer 2004; 112: 420-425.
15. Chen T, Jackson CR, Link A, et al. Int7G24A variant of transforming growth factor-beta receptor type I is associated with invasive breast cancer. Clin Cancer Res 2006; 12: 392-397.
16. You W, Liu Z, Zhao J, et al. No association between TGFBR1*6A and lung cancer. J Thorac Oncol 2007; 2: 657-659.
17. Zhang HT, Fei QY, Chen F, et al. Mutational analysis of the transforming growth factor beta receptor type I gene in primary non-small cell lung cancer. Lung Cancer 2003; 40: 281-287.
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28. Chen T, Triplett J, Dehner B, et al. Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas. Cancer Res 2001; 61: 4679-4682.
29. Wang D, Kanuma T, Mizunuma H, et al. Analysis of specific gene mutations in the transforming growth factor-beta signal transduction pathway in human ovarian cancer. Cancer Res 2000; 60: 4507-4512.
30. Zeng Q, Phukan S, Xu Y, et al. Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development. Cancer Res 2009; 69: 678-686.
31. Valle L, Serena-Acedo T, Liyanarachchi S, et al. Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer. Science 2008; 321: 1361-1365.
32. Zhao J, Liu Z, Li W, Liu X, Chen XF, Zhang HT. Infrequently methylated event at sites -362 to -142 in the promoter of TGF beta R1 gene in non-small cell lung cancer. J Cancer Res Clin Oncol 2008; 134: 919-925.
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1. Pierce DF, Jr., Gorska AE, Chytil A, et al. Mammary tumor suppression by transforming growth factor beta 1 transgene expression. Proc Natl Acad Sci U S A 1995; 92: 4254-4258.
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1. Yang L, Parkin DM, Li LD, Chen YD, Bray F. Estimation and projection of the national profile of cancer mortality in China: 1991-2005. Br J Cancer 2004; 90: 2157-2166.
2. Shields PG. Molecular epidemiology of smoking and lung cancer. Oncogene 2002; 21: 6870-6876.
3. Park C, Kim WS, Choi Y, Kim H, Park K. Effects of transforming growth factor beta (TGF-beta) receptor on lung carcinogenesis. Lung Cancer 2002; 38: 143-147.
4. Zhao L, Sheldon K, Chen M, et al. The predictive role of plasma TGF-beta1 during radiation therapy for radiation-induced lung toxicity deserves further study in patients with non-small cell lung cancer. Lung Cancer 2008; 59: 232-239.
5. Knaus PI, Lindemann D, DeCoteau JF, 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: 3480-3489.
6. Kim IY, Ahn HJ, Lang S, et al. Loss of expression of transforming growth factor-beta receptors is associated with poor prognosis in prostate cancer patients. Clin Cancer Res 1998; 4: 1625-1630.
7. Tokunaga H, Lee DH, Kim IY, Wheeler TM, Lerner SP. Decreased expression of transforming growth factor beta receptor type I is associated with poor prognosis in bladder transitional cell carcinoma patients. Clin Cancer Res 1999; 5: 2520-2525.
8. Wagner M, Kleeff J, Friess H, Buchler MW, Korc M. Enhanced expression of the type II transforming growth factor-beta receptor is associated with decreased survival in human pancreatic cancer. Pancreas 1999; 19: 370-376.
9. Colasante A, Aiello FB, Brunetti M, di Giovine FS. Gene expression of transforming growth factor beta receptors I and II in non-small-cell lung tumors. Cytokine 2003; 24: 182-189.
10. Song B, Margolin S, Skoglund J, et al. TGFBR1(*)6A and Int7G24A variants of transforming growth factor-beta receptor 1 in Swedish familial and sporadic breast cancer. Br J Cancer 2007; 97: 1175-1179.
11. Baxter SW, Choong DY, Eccles DM, Campbell IG. Transforming growth factor beta receptor 1 polyalanine polymorphism and exon 5 mutation analysis in breast and ovarian cancer. Cancer Epidemiol Biomarkers Prev 2002; 11: 211-214.
12. Pasche B, Kolachana P, Nafa K, et al. TbetaR-I(6A) is a candidate tumor susceptibility allele. Cancer Res 1999; 59: 5678-5682.
13. Chen T, de Vries EG, Hollema H, et al. Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma. Int J Cancer 1999; 82: 43-51.
14. Chen T, Jackson C, Costello B, et al. An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder. Int J Cancer 2004; 112: 420-425.
15. Chen T, Jackson CR, Link A, et al. Int7G24A variant of transforming growth factor-beta receptor type I is associated with invasive breast cancer. Clin Cancer Res 2006; 12: 392-397.
16. You W, Liu Z, Zhao J, et al. No association between TGFBR1*6A and lung cancer. J Thorac Oncol 2007; 2: 657-659.
17. Zhang HT, Fei QY, Chen F, et al. Mutational analysis of the transforming growth factor beta receptor type I gene in primary non-small cell lung cancer. Lung Cancer 2003; 40: 281-287.
18. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263-265.
19. Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA. Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 2004; 74: 106-120.
20. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning. ed. NY: Cold Spring Harbor Laboratory; 1989.
21. Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 2005; 15: 97-98.
22. Hung RJ, Christiani DC, Risch A, et al. International lung cancer consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways. Cancer Epidemiol Biomarkers Prev 2008; 17: 3081-3089.
23. McKay JD, Hung RJ, Gaborieau V, et al. Lung cancer susceptibility locus at 5p15.33. Nat Genet 2008; 40: 1404-1406.
24. Akey J, Jin L, Xiong M. Haplotypes vs single marker linkage disequilibrium tests: what do we gain? Eur J Hum Genet 2001; 9: 291-300.
25. Tang B, Bottinger EP, Jakowlew SB, et al. Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat Med 1998; 4: 802-807.
26. Im YH, Kim HT, Kim IY, et al. Heterozygous mice for the transforming growth factor-beta type II receptor gene have increased susceptibility to hepatocellular carcinogenesis. Cancer Res 2001; 61: 6665-6668.
27. Chen T, Yan W, Wells RG, et al. Novel inactivating mutations of transforming growth factor-beta type I receptor gene in head-and-neck cancer metastases. Int J Cancer 2001; 93: 653-661.
28. Chen T, Triplett J, Dehner B, et al. Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas. Cancer Res 2001; 61: 4679-4682.
29. Wang D, Kanuma T, Mizunuma H, et al. Analysis of specific gene mutations in the transforming growth factor-beta signal transduction pathway in human ovarian cancer. Cancer Res 2000; 60: 4507-4512.
30. Zeng Q, Phukan S, Xu Y, et al. Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development. Cancer Res 2009; 69: 678-686.
31. Valle L, Serena-Acedo T, Liyanarachchi S, et al. Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer. Science 2008; 321: 1361-1365.
32. Zhao J, Liu Z, Li W, Liu X, Chen XF, Zhang HT. Infrequently methylated event at sites -362 to -142 in the promoter of TGF beta R1 gene in non-small cell lung cancer. J Cancer Res Clin Oncol 2008; 134: 919-925.
33. Pasche B, Kaklamani V, Hou N, et al. TGFBR1*6A and cancer: a meta-analysis of 12 case-control studies. J Clin Oncol 2004; 22: 756-758.
34. Zhang HT, Zhao J, Zheng SY, Chen XF. Is TGFBR1*6A really associated with increased risk of cancer? J Clin Oncol 2005; 23: 7743-7744; author reply 7744-7746.
35. Lucarini L, Sticchi E, Sofi F, et al. ACE and TGFBR1 genes interact in influencing the susceptibility to abdominal aortic aneurysm. Atherosclerosis 2008.
36. Pasche B, Knobloch TJ, Bian Y, et al. Somatic acquisition and signaling of TGFBR1*6A in cancer. JAMA 2005; 294: 1634-1646.
37. Rosman DS, Phukan S, Huang CC, Pasche B. TGFBR1*6A enhances the migration and invasion of MCF-7 breast cancer cells through RhoA activation. Cancer Res 2008; 68: 1319-1328.