前列腺癌易感位点rs2252004的eQTL和meQTL研究
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摘要
目的:全基因组关联性研究(GWAS)发现rs2252004与前列腺癌的易感性相关,本研究拟进一步探讨rs2252004参与前列腺癌发生的可能分子生物学机制。方法:运用TCGA公共数据库中的基因型、甲基化、基因表达数据,采用线性回归分析rs2252004基因型与其上下游1 Mb区域Cp G位点的甲基化水平及相关基因表达的关联性。结果:rs2252004与FGFR2基因上的3个Cp G位点的甲基化水平显著相关(cg25294906,P=0.031;cg03552039,P=0.042;cg16499947,P=0.049)。而FGFR2在50例配对的前列腺癌组织和癌旁组织中表达差异有统计学意义(P=9.3×10-11)。与GG基因型相比,rs2252004 GT基因型的前列腺癌患者的FGFR2基因表达量显著降低(P=0.007)。此外,GT/TT基因型与GG基因型患者的FGFR2表达量差异有统计学意义(P=0.006)。结论:rs2252004可能通过影响FGFR2甲基化水平,进而调控FGFR2基因的表达,从而参与前列腺癌的发生。
Objective:Previous genome-wide association study(GWAS)has identified that rs2252004 was associated with the susceptibility of prostate cancer. This study was aimed to investigate the molecular biological mechanisms underlying the effect of rs2252004 on tumorigenesis of prostate cancer. Methods:We obtained the genotype,methylation and gene expression data from The Cancer Genome Atlas(TCGA)database. The relationships between rs2252004 genotype(0,1,or 2)and the β-value or proportion of methylation at each Cp G site(within 500 kb of rs2252004)and the expression level of involved genes were evaluated via linear regression. Results:The results showed that rs2252004 was significantly associated with the methylation level of three Cp G cites located in FGFR2(cg25294906,P=0.031;cg03552039,P=0.042;cg16499947,P=0.049,respectively). Furthermore,the expression of FGFR2 remarkably differed between 50 paired prostate tumors and adjacent normal tissues(P=9.3×10-11). Besides,individuals carrying rs2252004 GT genotypes were significantly associated with decreased expression of FGFR2 than those with GG genotypes(P=0.007).We also observed a notable different expression of FGFR2 between GT/TT genotype and GG genotype individuals(P=0.006).Conclusion:Altogether,our results suggest that rs2252004 may regulate the methylation level of FGFR2,which contributes to influence FGFR2 expression,thus be involved in the tumorigenesis of prostate cancer.
Objective:Previous genome-wide association study(GWAS)has identified that rs2252004 was associated with the susceptibility of prostate cancer. This study was aimed to investigate the molecular biological mechanisms underlying the effect of rs2252004 on tumorigenesis of prostate cancer. Methods:We obtained the genotype,methylation and gene expression data from The Cancer Genome Atlas(TCGA)database. The relationships between rs2252004 genotype(0,1,or 2)and the β-value or proportion of methylation at each Cp G site(within 500 kb of rs2252004)and the expression level of involved genes were evaluated via linear regression. Results:The results showed that rs2252004 was significantly associated with the methylation level of three Cp G cites located in FGFR2(cg25294906,P=0.031;cg03552039,P=0.042;cg16499947,P=0.049,respectively). Furthermore,the expression of FGFR2 remarkably differed between 50 paired prostate tumors and adjacent normal tissues(P=9.3×10-11). Besides,individuals carrying rs2252004 GT genotypes were significantly associated with decreased expression of FGFR2 than those with GG genotypes(P=0.007).We also observed a notable different expression of FGFR2 between GT/TT genotype and GG genotype individuals(P=0.006).Conclusion:Altogether,our results suggest that rs2252004 may regulate the methylation level of FGFR2,which contributes to influence FGFR2 expression,thus be involved in the tumorigenesis of prostate cancer.
引文
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[14]Hancock DB,Wang JC,Gaddis NC,et al.A multiancestry study identifies novel genetic associations with CHRNA5methylation in human brain and risk of nicotine dependence[J].Hum Mol Genet,2015,24(20):5940-5954
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[18]Zhang X,Ibrahimi OA,Olsen SK,et al.Receptor specificity of the fibroblast growth factor family.The complete mammalian FGF family[J].J Biol Chem,2006,281(23):15694-15700
[19]Matsubara A,Kan M,Feng SJ,et al.Inhibition of growth of malignant rat prostate tumor cells by restoration of fibroblast growth factor receptor 2[J].Cancer Res,1998,58(7):1509-1514
[20]Ricol D,Cappellen D,El Marjou A,et al.Tumour suppressive properties of fibroblast growth factor receptor 2-IIIb in human bladder cancer[J].Oncogene,1999,18(51):7234-7243
[2]Torre LA,Bray F,Siegel RL,et al.Global cancer statistics,2012[J].CA Cancer J Clin,2015,65(2):87-108
[3]Lichtenstein P,Holm NV,Verkasalo PK,et al.Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden,Denmark,and Finland[J].N Engl J Med,2000,343(2):78-85
[4]Hindorff LA,Sethupathy P,Junkins HA,et al.Potential etiologic and functional implications of genome-wide association loci for human diseases and traits[J].Proc Natl Acad Sci U S A,2009,106(23):9362-9367
[5]Takata R,Akamatsu S,Kubo M,et al.Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population[J].Nat Genet,2010,42(9):751-754
[6]Xu J,Mo Z,Ye D,et al.Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4[J].Nat Genet,2012,44(11):1231-1235
[7]Akamatsu S,Takata R,Haiman CA,et al.Common variants at 11q12,10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese[J].Nat Genet,2012,44(4):426-429
[8]Wang ML,Takahashi A,Liu F,et al.Large-scale association analysis in Asians identifies new susceptibility loci for prostate cance[rJ].Nat Commun,2015,6:8469
[9]Rockman MV,Kruglyak L.Genetics of global gene expression[J].Nat Rev Genet,2006,7(11):862-872
[10]Rushton MD,Reynard LN,Young DA,et al.Methylation quantitative trait locus analysis of osteoarthritis links epigenetics with genetic risk[J].Hum Mol Genet,2015,24(25):7432-7444
[11]Gu X,Huang T,Xu D,et al.Association of a common variant at 10q26 and benign prostatic hyperplasia aggressive-ness in han Chinese descent[J].Biochem Res Int,2013,2013:820849
[12]Rivas MA,Beaudoin M,Gardet A,et al.Deep resequencing of GWAS loci identifies Independent rare variants associated with inflammatory bowel disease[J].Nat Genet,2011,43(11):1066-1073
[13]Nicolae DL,Gamazon E,Zhang W,et al.Trait-Associated SNPs are more likely to be e QTLs:annotation to enhance discovery from GWAS[J].PLo S Genet,2010,6(4):e1000888
[14]Hancock DB,Wang JC,Gaddis NC,et al.A multiancestry study identifies novel genetic associations with CHRNA5methylation in human brain and risk of nicotine dependence[J].Hum Mol Genet,2015,24(20):5940-5954
[15]Katoh M,Katoh M.FGFR2 and WDR11 are neighboring oncogene and tumor suppressor gene on human chromosome 10q26[J].Int J Oncol,2003,22(5):1155-1159
[16]Ittmann M.Allelic loss on chromosome 10 in prostate adenocarcinoma[J].Cancer Res,1996,56(9):2143-2147
[17]Dionne CA,Crumley G,Bellot F,et al.Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors[J].EMBO J,1990,9(9):2685-2692
[18]Zhang X,Ibrahimi OA,Olsen SK,et al.Receptor specificity of the fibroblast growth factor family.The complete mammalian FGF family[J].J Biol Chem,2006,281(23):15694-15700
[19]Matsubara A,Kan M,Feng SJ,et al.Inhibition of growth of malignant rat prostate tumor cells by restoration of fibroblast growth factor receptor 2[J].Cancer Res,1998,58(7):1509-1514
[20]Ricol D,Cappellen D,El Marjou A,et al.Tumour suppressive properties of fibroblast growth factor receptor 2-IIIb in human bladder cancer[J].Oncogene,1999,18(51):7234-7243