Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal cancer.
Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal cancer.
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DOI：
10.1186/s13148-018-0578-9
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发表时间：
2018-12-04
影响因子：
5.7
通讯作者：
Soejima H
中科院分区：
文献类型：
--
作者：
Hidaka H;Higashimoto K;Aoki S;Mishima H;Hayashida C;Maeda T;Koga Y;Yatsuki H;Joh K;Noshiro H;Iwakiri R;Kawaguchi A;Yoshiura KI;Fujimoto K;Soejima H
印迹基因受印迹相关差异甲基化区（iDMRs）的DNA甲基化调控。印迹基因的异常表达与印迹疾病和肿瘤有关。在结直肠癌（CRC）中，IGF2/H19结构域的甲基化和印迹状态已经被研究。然而，CRC中iDMRs的全面甲基化分析尚未报道。此外，iDMR甲基化状态与其他甲基化相关问题（如CpG岛甲基化表型（CIMP）和长穿插元件-1 （LINE-1）甲基化）之间的关系尚不清楚。我们分析了106例结直肠癌患者中38个iDMRs的甲基化状态。我们还研究了CIMP、LINE-1甲基化、KRAS和BRAF基因突变以及IGF2的印迹缺失（LOI）。我们进一步研究了这些因素与临床病理因素之间的关系。iDMR甲基化的总体趋势是向高甲基化方向发展，iDMR可分为易感、耐药和中间至异常甲基化三类。易感和抗性iDMR包括所有类型的iDMR（配子和体细胞，母系和父系甲基化）。多个iDMRs （HyMiD）阳性状态的高甲基化与cimp阳性状态相关，但与BRAF和KRAS基因突变无关。hymid阳性状态与LINE-1甲基化呈负相关。在IGF2/H19结构域的4个iDMRs中，IGF2- dmr0低甲基化发生最频繁，但与IGF2 LOI无关。最后，我们根据三种iDMRs的异常甲基化状态统计计算预测预后评分。在结直肠癌组织中，一些iDMR易发生超甲基化，与iDMR的类型和基因组序列无关。尽管hymid阳性状态与CIMP阳性状态相关，但这与负责CIMP的BRAF和KRAS通路无关。由于IGF2- dmr0低甲基化和IGF2/H19结构域内其他iDMRs的异常甲基化与IGF2 LOI无关，因此任何与印迹调控相关的分子组分的功能障碍都可能参与IGF2 LOI。基于三种iDMRs的异常甲基化计算的预后评分作为患者的预后预测指标具有潜在的临床应用价值。需要进一步的研究来了解iDMRs和IGF2 LOI在crc中的异常甲基化的生物学意义及其背后的机制。本文的在线版本（10.1186/s13148-018-0578-9）包含补充材料，授权用户可使用。
Imprinted genes are regulated by DNA methylation at imprinting-associated differentially methylated regions (iDMRs). Abnormal expression of imprinted genes is implicated in imprinting disorders and tumors. In colorectal cancer (CRC), methylation and imprinting status of the IGF2/H19 domain have been studied. However, no comprehensive methylation analysis of iDMRs in CRC has been reported. Furthermore, the relationship between iDMR methylation status and other methylation-related issues, such as CpG island methylator phenotype (CIMP) and long interspersed element-1 (LINE-1) methylation, remains unclear. We analyzed the methylation status of 38 iDMRs in 106 CRC patients. We also investigated CIMP, LINE-1 methylation, KRAS and BRAF gene mutations, and loss of imprinting (LOI) of IGF2. We further examined the relationship between these factors and clinicopathological factors. The overall trend in iDMR methylation was towards hypermethylation, and iDMRs could be grouped into three categories: susceptible, resistant, and intermediate-to-aberrant methylation. The susceptible and resistant iDMRs consisted of all types of iDMR (gametic and somatic, maternally and paternally methylated). Hypermethylation of multiple iDMRs (HyMiD)-positive status was statistically associated with CIMP-positive status, but not associated with mutations in the BRAF and KRAS genes. HyMiD-positive status was inversely associated with LINE-1 methylation. Among four iDMRs within the IGF2/H19 domain, IGF2-DMR0 hypomethylation occurred most frequently, but was not associated with IGF2 LOI. Finally, we statistically calculated predictive prognostic scores based on aberrant methylation status of three iDMRs. In CRC tissues, some iDMRs were susceptible to hypermethylation independent of the type of iDMR and genomic sequence. Although HyMiD-positive status was associated with CIMP-positive status, this was independent of the BRAF and KRAS pathways, which are responsible for CIMP. Since IGF2-DMR0 hypomethylation and aberrant methylation of other iDMRs within the IGF2/H19 domain were not associated with IGF2 LOI, dysfunction of any of the molecular components related to imprinting regulation may be involved in IGF2 LOI. The prognostic score calculated based on aberrant methylation of three iDMRs has potential clinical applications as a prognostic predictor in patients. Further study is required to understand the biological significance of, and mechanisms behind, aberrant methylation of iDMRs and IGF2 LOI in CRCs. The online version of this article (10.1186/s13148-018-0578-9) contains supplementary material, which is available to authorized users.
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影响因子：
4.8
作者：
Dalai, Irene;Missiaglia, Edoardo;Scarpa, Aldo
通讯作者：
Scarpa, Aldo
影响因子：
56.9
作者：
Cui, HM;Cruz-Correa, M;Feinberg, AP
通讯作者：
Feinberg, AP
影响因子：
14.9
作者：
Kim J;Bretz CL;Lee S
通讯作者：
Lee S
影响因子：
3.7
作者：
Estecio, Marcos R. H.;Gharibyan, Vazganush;Shen, Lanlan;Ibrahim, Ashraf E. K.;Doshi, Ketan;He, Rong;Jelinek, Jaroslav;Yang, Allen S.;Yan, Pearlly S.;Huang, Tim H-M.;Tajara, Eloiza H.;Issa, Jean-Pierre J.
通讯作者：
Issa, Jean-Pierre J.
影响因子：
6.4
作者：
Cheng, Yu-Wei;Idrees, Kamran;Shattock, Richard;Khan, Sajid A.;Zeng, Zhaoshi;Brennan, Cameron W.;Paty, Philip;Barany, Francis
通讯作者：
Barany, Francis