Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients.
Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients.
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DOI：
10.1093/hmg/ddp033
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发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Petronis A
中科院分区：
文献类型：
--
作者：
Flanagan JM;Munoz-Alegre M;Henderson S;Tang T;Sun P;Johnson N;Fletcher O;Dos Santos Silva I;Peto J;Boshoff C;Narod S;Petronis A
乳腺癌的双侧性是体质癌症易感性的一个指标；然而，在大多数病例中，这种易感性背后的分子原因尚不清楚。我们假设癌症相关基因的表观遗传失调可能是这种易感性的部分原因。我们对14例双侧乳腺癌患者和14例正常对照的外周血DNA进行了甲基化微阵列分析，检测了17个候选乳腺癌易感基因，包括BRCA1、BRCA2、CHEK2、ATM、ESR1、SFN、CDKN2A、TP53、GSTP1、CDH1、CDH13、HIC1、PGR、SFRP1、MLH1、RARB和HSD17B4。我们发现大多数甲基化变异与基因内重复元件有关。对190名双侧乳腺癌患者和190名对照组的相同样本和第二组外周血DNA进行亚硫酸氢盐修饰和焦磷酸测序，对ATM周围的平铺区域进行详细验证。我们发现乳腺癌患者中一个基因内重复元件的甲基化显著高于对照组(P=0.0017)，甲基化的最高四分位与乳腺癌风险增加3倍相关(OR3.2，95%CI1.78-5.86，P=0.000083)。该基因的甲基化增加与较低的稳态ATM mRNA水平相关，并与癌症患者的年龄相关，但与对照组无关，这表明与年龄-表型相关的联合关联。这项研究证明了外周血DNA中ATM和其他癌症相关基因的基因-体表遗传学错误调节的可能性，这些基因可能作为一种新的标记来评估乳腺癌的风险。登录号：微阵列数据和相关的.BED和.WIG文件可通过基因表达总括登录号：GSE14603获得。
Bilaterality of breast cancer is an indicator of constitutional cancer susceptibility; however, the molecular causes underlying this predisposition in the majority of cases is not known. We hypothesize that epigenetic misregulation of cancer-related genes could partially account for this predisposition. We have performed methylation microarray analysis of peripheral blood DNA from 14 women with bilateral breast cancer compared with 14 unaffected matched controls throughout 17 candidate breast cancer susceptibility genes including BRCA1, BRCA2, CHEK2, ATM, ESR1, SFN, CDKN2A, TP53, GSTP1, CDH1, CDH13, HIC1, PGR, SFRP1, MLH1, RARB and HSD17B4. We show that the majority of methylation variability is associated with intragenic repetitive elements. Detailed validation of the tiled region around ATM was performed by bisulphite modification and pyrosequencing of the same samples and in a second set of peripheral blood DNA from 190 bilateral breast cancer patients compared with 190 controls. We show significant hypermethylation of one intragenic repetitive element in breast cancer cases compared with controls (P = 0.0017), with the highest quartile of methylation associated with a 3-fold increased risk of breast cancer (OR 3.20, 95% CI 1.78–5.86, P = 0.000083). Increased methylation of this locus is associated with lower steady-state ATM mRNA level and correlates with age of cancer patients but not controls, suggesting a combined age–phenotype-related association. This research demonstrates the potential for gene-body epigenetic misregulation of ATM and other cancer-related genes in peripheral blood DNA that may be useful as a novel marker to estimate breast cancer risk. Accession numbers: The microarray data and associated .BED and .WIG files can be accessed through Gene Expression Omnibus accession number: GSE14603.
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影响因子：
2.5
作者：
Morgan, Daniel K.;Whitelaw, Emma
通讯作者：
Whitelaw, Emma
影响因子：
56.9
作者：
Cui, HM;Cruz-Correa, M;Feinberg, AP
通讯作者：
Feinberg, AP
间充质肿瘤的分子图。
影响因子：
12.3
作者：
Henderson, Stephen R;Guiliano, David;Presneau, Nadege;McLean, Sean;Frow, Richard;Vujovic, Sonja;Anderson, John;Sebire, Neil;Whelan, Jeremy;Athanasou, Nick;Flanagan, Adrienne M;Boshoff, Chris
通讯作者：
Boshoff, Chris
影响因子：
12.3
作者：
Flanagan, James M;Wild, Laurence
通讯作者：
Wild, Laurence
DOI：
10.1073/pnas.0500398102
发表时间：
2005-07-26
影响因子：
11.1
作者：
Fraga, MF;Ballestar, E;Esteller, M
通讯作者：
Esteller, M