Genome-wide methylation screen in low-grade breast cancer identifies novel epigenetically altered genes as potential biomarkers for tumor diagnosis
Genome-wide methylation screen in low-grade breast cancer identifies novel epigenetically altered genes as potential biomarkers for tumor diagnosis
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DOI：
10.1096/fj.12-209502
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发表时间：
2012-12-01
期刊：
影响因子：
4.8
通讯作者：
Gerhauser, Clarissa
中科院分区：
文献类型：
--
作者：
Faryna, Marta;Konermann, Carolin;Gerhauser, Clarissa
异常DNA甲基化构成了乳腺癌的一个公认的表观遗传标记。癌症发展早期甲基化的变化可能与癌症检测和基于预后的治疗决策具有临床相关性。在本研究中，采用甲基-CpG免疫沉淀（MCIp）和人CpG岛（CGI）阵列相结合的方法，比较了10例低级别原位和侵袭性乳腺癌与10例正常乳腺样本的全基因组DNA甲基化谱。总共有214个cgi在10个肿瘤中的>= 6中被发现高甲基化。功能项富集分析显示同源盒基因和参与转录和调控转录的基因过多。使用定量EpiTyper技术，在两个独立的样本集（45个肿瘤和11个对照组，43个肿瘤和8个对照组）中验证了肿瘤中11个选定基因与正常组织的显著高甲基化。在肿瘤中，BCAN、HOXD1、KCTD8、KLF11、NXPH1、POU4F1、SIM1和TCF7L1的中位甲基化水平比正常样本高>= 30%，代表了肿瘤诊断的潜在生物标志物。以正常组织中甲基化水平的第90百分位作为截断值，原位样本（n = 13）的62-92%，第一个验证集（n = 32）的72-97%，第二个验证集（n = 43）的86-100%的侵入性样本被归类为高甲基化。KLF11和SIM1的高甲基化也可能与发生转移的风险增加有关。总之，早期甲基化变化在乳腺癌低级别通路中很常见，可能对鉴别诊断和预后标志物的发展有用。-Faryna， M., Konermann， C., auulmann， S., Bermejo， J., Brugger， M., Diederichs， S., Rom， J., Weichenhan， D., Claus， R., Rehli， M., Schirmacher， P., Sinn, h . P.低级别乳腺癌的全基因组甲基化筛查发现新的表观遗传改变基因作为肿瘤诊断的潜在生物标志物。中国生物医学工程学报，26(4):437 - 450（2012）。www.fasebj.org
Aberrant DNA methylation constitutes a well-established epigenetic marker for breast cancer. Changes in methylation early in cancer development may be clinically relevant for cancer detection and prognosis-based therapeutic decisions. In the present study, a combination of methyl-CpG immunoprecipitation (MCIp) and human CpG island (CGI) arrays was applied to compare genome-wide DNA methylation profiles in 10 low-grade in situ and invasive breast cancers against 10 normal breast samples. In total, 214 CGIs were found to be hypermethylated in >= 6 of 10 tumors. Functional term enrichment analyses revealed an overrepresentation of homeobox genes and genes involved in transcription and regulation of transcription. Significant hypermethylation of 11 selected genes in tumor vs. normal tissue was validated in two independent sample sets (45 tumors and 11 controls, 43 tumors and 8 controls) using quantitative EpiTyper technology. In tumors, median methylation levels of BCAN, HOXD1, KCTD8, KLF11, NXPH1, POU4F1, SIM1, and TCF7L1 were >= 30% higher than in normal samples, representing potential biomarkers for tumor diagnosis. Using the 90th percentile of methylation levels in normal tissue as cutoff value, 62-92% of in situ samples (n = 13), 72-97% of invasive samples from the first validation set (n = 32), and 86-100% of invasive samples from the second validation set (n = 43) were classified as hypermethylated. Hypermethylation of KLF11 and SIM1 might also be associated with increased risk of developing metastases. In summary, early methylation changes are frequent in the low-grade pathway of breast cancer and may be useful in the development of differential diagnostic and possibly also prognostic markers.-Faryna, M., Konermann, C., Aulmann, S., Bermejo, J. L., Brugger, M., Diederichs, S., Rom, J., Weichenhan, D., Claus, R., Rehli, M., Schirmacher, P., Sinn, H.-P., Plass, C., Gerhauser, C. Genome-wide methylation screen in low-grade breast cancer identifies novel epigenetically altered genes as potential biomarkers for tumor diagnosis. FASEB J. 26, 4937-4950 (2012). www.fasebj.org