基于生物信息学的肝癌易感基因ARID1A低频遗传变异的功能分析
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摘要
目的运用生物信息学方法对肝癌易感基因ARID1A的低频遗传变异进行功能初探,为后续肝癌遗传关联研究提供线索。方法运用1000 genomes、db SNP、UCSC等数据库检索ARID1A的低频遗传变异名录;通过Regulome DB、SNPinfo、F-SNP等功能注释数据库预测低频变异的功能。结果在1000 genomes的中国汉族南方人群和中国汉族北方人群数据中,ARID1A基因上MAF≤0.05的遗传变异各有141和139个,其中135个低频变异位于调控区或编码区。Regulome DB、SNPinfo、F-SNP等数据库预测出9个潜在功能变异,分别为rs12685、rs60798877、rs6598860、rs12739212、rs139907456、rs34618114、rs191813608、rs182858322和rs78520390。结论所识别的ARID1A基因的9个低频潜在功能变异,可作为肝癌遗传关联研究的目标变异,以助于系统阐明ARID1A低频变异对肝癌易感性的影响。
Objective To analyze the low-frequency variations in the liver cancer susceptibility gene ARID1A using a comprehensive bioinformatics strategy,and provide a clue for the genetic association studies of liver cancer. Methods 1000 Genomes Project,db SNP,UCSC and other databases were applied to query the list of low-frequency variants. Allele frequency calculator was used to select the variants with the minor allele frequency( MAF) ≤ 5%. Regulome DB, SNPinfo, F-SNP and other tools were utilized to predict the function of low-frequency variants. Results There were 141 and 139 variants with the MAF ≤5% in the CHS and CHB data of 1000 genomes, respectively, in which 135 variants were located in the regulatory region or coding region. Nine variants had been predicted to be potential functional by Regulome DB,SNPinfo,F-SNP and other tools. Conclusion The potentially functional variants in ARID1A with lowfrequency could be used as targets in the genetic association studies of liver cancer,which may provide an evidence for exploring the effect of ARID1A low-frequency variants on the development of liver cancer.
Objective To analyze the low-frequency variations in the liver cancer susceptibility gene ARID1A using a comprehensive bioinformatics strategy,and provide a clue for the genetic association studies of liver cancer. Methods 1000 Genomes Project,db SNP,UCSC and other databases were applied to query the list of low-frequency variants. Allele frequency calculator was used to select the variants with the minor allele frequency( MAF) ≤ 5%. Regulome DB, SNPinfo, F-SNP and other tools were utilized to predict the function of low-frequency variants. Results There were 141 and 139 variants with the MAF ≤5% in the CHS and CHB data of 1000 genomes, respectively, in which 135 variants were located in the regulatory region or coding region. Nine variants had been predicted to be potential functional by Regulome DB,SNPinfo,F-SNP and other tools. Conclusion The potentially functional variants in ARID1A with lowfrequency could be used as targets in the genetic association studies of liver cancer,which may provide an evidence for exploring the effect of ARID1A low-frequency variants on the development of liver cancer.
引文
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[3]WILSON B G,ROBERTS C W M.SWI/SNF nucleosome remodellers and cancer[J].Nat Rev Cancer,2011,11(7):481-492.
[4]LUCHINI C,VERONESE N,SOLMI M,et al.Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer:a systematic review and meta-analysis[J].Oncotarget,2015,6(36):39088-39097.
[5]KITTS A,PHAN L,WARD M,et al.The Database of short genetic variation(db SNP).In:The NCBI Handbook[Internet].2nd edition.Bethesda(MD):National Center for Biotechnology Information(US),2013:1-41.
[6]TYNER C,BARBER G P,CASPER J,et al.The UCSC genome browser database:2017 update[J].Nucleic Acids Res,2017,45:D626-D634.
[7]国际千人基因组计划[EB/OL].(2010-06-22)[2017-01-10].http://www.51qe.cn/med/2010/118101.html.
[8]BOYLE A P,HONG E L,HARIHARAN M,et al.Annotation of functional variation in personal genomes using Regulome DB[J].Genome Res,2012,22(9):1790-1797.
[9]WARD L D,KELLIS M.HaploReg v4:systematic mining of putative causal variants,cell types,regulators and target genes for human complex traits and disease[J].Nucleic Acids Res,2016,44(D1):D877-D881.
[10]YATES A,AKANNI W,AMODE M R,et al.Ensembl 2016[J].Nucleic Acids Res,2016,44(D1):D710-D716.
[11]XU Zongli,TAYLOR J A.SNPinfo:integrating GWAS and candidate gene information into functional SNP selection for genetic association studies[J].Nucleic Acids Res,2009,37(Web Server):W600-W605.
[12]LEE P H,SHATKAY H.F-SNP:computationally predicted functional SNPs for disease association studies[J].Nucleic Acids Res,2007,36(Database):D820-D824.
[13]GUO Liyuan,DU Yang,CHANG Suhua,et al.r SNPBase:a database for curated regulatory SNPs[J].Nucleic Acids Res,2013,42(D1):D1033-D1039.
[14]LIU Ning,BALLIANO A,HAYES J J.Mechanism(s)of SWI/SNF-induced nucleosome mobilization[J].Chembiochem,2011,12(2):196-204.
[15]SKULTE K A,PHAN L,CLARK S J,et al.Chromatin remodeler mutations in human cancers:epigenetic implications[J].Epigenomics,2014,6(4):397-414.
[16]HOTA S K,BRUNEAU B G.ATP-dependent chromatin remodeling during mammalian development[J].Development,2016,143(16):2882-2897.
[17]FUJIMOTO A,TOTOKI Y,ABE T,et al.Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators[J].Nat Genet,2012,44(7):760-764.
[18]HUANG Jian,DENG Qing,WANG Qun,et al.Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma[J].Nat Genet,2012,44(10):1117-1121.
[19]LEE S Y,KIM D,LEE H S,et al.Loss of AT-Rich interactive domain 1A expression in gastrointestinal malignancies[J].Oncology,2015,88(4):234-240.
[20]JONES S,WANG Tianli,SHIH I M,et al.Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma[J].Science,2010,330(6001):228-231.
[21]李婷,邢宝玲,葛素梅,等.子宫内膜样腺癌中ARID1A蛋白的表达及意义[J].临床与实验病理学杂志,2016,32(3):287-291.
[22]GUI Yaoting,GUO Guangwu,HUANG Yi,et al.Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder[J].Nat Genet,2011,43(9):875.
[23]WANG Kai,KAN Junsuo,Yuen Siutsan,et al.Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer[J].Nat Genet,2011,43(12):1219-1223.
[24]JONES S,LI Meng,PARSONS D W,et al.Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types[Z].2012,33:100-103.