Whole genome DNA methylation signature of HER2-positive breast cancer

Lindqvist, Breezy Malakkaran; Wingren, Sten; Motlagh, Parviz Behnam; Nilsson, Torbjörn

doi:10.4161/epi.29632

Cited by 51 publications

(55 citation statements)

References 49 publications

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“…DNA methylation aberrations have been found to have critical roles in the pathogenesis of many tumor models. 16,17 However, an early study by Uhlmann et al 18 showed no evidence of CpG island hypermethylation in PA. Recently, Lambert et al 9 found that infratentorial PA showed hypomethylation level compared with supratentorial PA, and methylation levels in tumor tissues were associated with the locations of PA occurrence.…”

Section: Introductionmentioning

confidence: 97%

Screening genes crucial for pediatric pilocytic astrocytoma using weighted gene coexpression network analysis combined with methylation data analysis

Zhao

Cai

et al. 2014

Cancer Gene Ther

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To identify novel genes associated with pediatric pilocytic astrocytoma (PA) for better understanding the molecular mechanism underlying the pediatric PA pathogenesis. Gene expression profile data of GSE50161 and GSE44971 and the methylation data of GSE44684 were downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) between PA and normal control samples were screened using the limma package in R, and then used to construct weighted gene coexpression network (WGCN) using the WGCN analysis (WGCNA) package in R. Significant modules of DEGs were selected using the clustering analysis. Function enrichment analysis of the DEGs in significant modules were performed using the WGCNA package and clusterprofiler package in R. Correlation between methylation sites of DEGs and PA was analyzed using the CpGassoc package in R. Totally, 3479 DEGs were screened in PA samples. Thereinto, 3424 DEGs were used to construct the WGCN. Several significant modules of DEGs were selected based on the WGCN, in which the turquoise module was positively related to PA, whereas blue module was negatively related to PA. DEGs (for example, DOCK2 (dedicator of cytokinesis 2), DOCK8 and FCGR2A (Fc fragment of IgG, low affinity IIa)) in blue module were mainly involved in Fc gamma R-mediated phagocytosis pathway and natural killer cell-mediated cytotoxicity pathway. Methylations of 14 DEGs among the top 30 genes in blue module were related to PA. Our data suggest that DOCK2, DOCK8 and FCGR2A may represent potential therapeutic targets in PA that merits further investigation.

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Section: Introductionmentioning

confidence: 97%

Screening genes crucial for pediatric pilocytic astrocytoma using weighted gene coexpression network analysis combined with methylation data analysis

Zhao

Cai

et al. 2014

Cancer Gene Ther

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“…In the case of some genes like AKT3 , CEMIP and DDR1 , promoter hypomethylation was observed in different types of cancers such as breast cancer, lung cancer and CRC[47-49]. PI3K/Akt pathway is thought to be the most commonly activated intracellular signaling pathway in human malignancies[50].…”

Section: Discussionmentioning

confidence: 99%

Aging related methylation influences the gene expression of key control genes in colorectal cancer and adenoma

Galamb

Kalmár

Barták

et al. 2016

WJG

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AIMTo analyze colorectal carcinogenesis and age-related DNA methylation alterations of gene sequences associated with epigenetic clock CpG sites.METHODSIn silico DNA methylation analysis of 353 epigenetic clock CpG sites published by Steve Horvath was performed using methylation array data for a set of 123 colonic tissue samples [64 colorectal cancer (CRC), 42 adenoma, 17 normal; GEO accession number: GSE48684]. Among the differentially methylated age-related genes, secreted frizzled related protein 1 (SFRP1) promoter methylation was further investigated in colonic tissue from 8 healthy adults, 19 normal children, 20 adenoma and 8 CRC patients using bisulfite-specific PCR followed by methylation-specific high resolution melting (MS-HRM) analysis. mRNA expression of age-related “epigenetic clock” genes was studied using Affymetrix HGU133 Plus2.0 whole transcriptome data of 153 colonic biopsy samples (49 healthy adult, 49 adenoma, 49 CRC, 6 healthy children) (GEO accession numbers: GSE37364, GSE10714, GSE4183, GSE37267). Whole promoter methylation analysis of genes showing inverse DNA methylation-gene expression data was performed on 30 colonic samples using methyl capture sequencing.RESULTSFifty-seven age-related CpG sites including hypermethylated PPP1R16B, SFRP1, SYNE1 and hypomethylated MGP, PIPOX were differentially methylated between CRC and normal tissues (P < 0.05, Δβ ≥ 10%). In the adenoma vs normal comparison, 70 CpG sites differed significantly, including hypermethylated DKK3, SDC2, SFRP1, SYNE1 and hypomethylated CEMIP, SPATA18 (P < 0.05, Δβ ≥ 10%). In MS-HRM analysis, the SFRP1 promoter region was significantly hypermethylated in CRC (55.0% ± 8.4 %) and adenoma tissue samples (49.9% ± 18.1%) compared to normal adult (5.2% ± 2.7%) and young (2.2% ± 0.7%) colonic tissue (P < 0.0001). DNA methylation of SFRP1 promoter was slightly, but significantly increased in healthy adults compared to normal young samples (P < 0.02). This correlated with significantly increased SFRP1 mRNA levels in children compared to normal adult samples (P < 0.05). In CRC tissue the mRNA expression of 117 age-related genes were changed, while in adenoma samples 102 genes showed differential expression compared with normal colonic tissue (P < 0.05, logFC > 0.5). The change of expression for several genes including SYNE1, CLEC3B, LTBP3 and SFRP1, followed the same pattern in aging and carcinogenesis, though not for all genes (e.g., MGP).CONCLUSIONSeveral age-related DNA methylation alterations can be observed during CRC development and progression affecting the mRNA expression of certain CRC- and adenoma-related key control genes.

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“…Previous studies showed that ERBB2 amplification frequently associates with DNA hypermethylation in human breast cancers . Other studies also have shown a number of hypermethylated genes in ErbB2‐positive breast cancer cells . In addition, DNA hypermethylation‐associated repression of tumor suppressor genes has been reported to be essential for Ras‐mediated transformation .…”

Section: Resultsmentioning

confidence: 98%

ErbB2 signaling epigenetically suppresses microRNA‐205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer

et al. 2017

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We previously reported that micro RNA ‐205 (miR‐205) is downregulated by overexpression of the receptor tyrosine kinase ErbB2 and that ectopic transfection of miR‐205 precursor decreases ErbB2 tumorigenicity in soft agar. In this study, we further analyzed the regulatory mechanisms linking ErbB2 overexpression and miR‐205 downregulation. In ErbB2‐overexpressing breast epithelial cells, miR‐205 expression was significantly increased by treatment with MEK inhibitor U0126 or PD 98059, Raf‐1 inhibitor ZM ‐336372, and ERK inhibitor SCH 772984, but PI 3K inhibitor LY 294002 and p38 MAPK inhibitor SB 203580 had no effect. We established breast epithelial cells overexpressing Raf CAAX , a constitutively active form of Raf‐1, and showed that overexpression of Raf CAAX dramatically reduced miR‐205 expression. In Raf CAAX ‐overexpressing cells, miR‐205 expression was also significantly increased by SCH 772984. Moreover, miR‐205 expression was significantly increased by treatment with DNA methyltransferase ( DNMT ) inhibitor 5‐aza‐2′‐deoxycytidine and expression of several DNMT family members was increased in both ErbB2‐ and Raf CAAX ‐overexpressing cells. DNA methylation analysis by bisulfite sequencing revealed that the putative miR‐205 promoters were predominantly hypermethylated in both ErbB2‐ and Raf CAAX ‐overexpressing cells. Reporter activity of the putative miR‐205 promoters was reduced in both ErbB2‐overexpressing and Raf CAAX ‐overexpressing cells. Together, these findings indicate that ErbB2 signaling epigenetically suppresses miR‐205 transcription via the Ras/Raf/ MEK / ERK pathway.

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Whole genome DNA methylation signature of HER2-positive breast cancer

Cited by 51 publications

References 49 publications

Screening genes crucial for pediatric pilocytic astrocytoma using weighted gene coexpression network analysis combined with methylation data analysis

Screening genes crucial for pediatric pilocytic astrocytoma using weighted gene coexpression network analysis combined with methylation data analysis

Aging related methylation influences the gene expression of key control genes in colorectal cancer and adenoma

ErbB2 signaling epigenetically suppresses microRNA‐205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer

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