Methylation of homeobox genes is a frequent and early epigenetic event in breast cancer

Tommasi, Stefania; Karm, Deborah L; Wu, Xiwei; Yen, Yun; Pfeifer, Gerd P.

doi:10.1186/bcr2233

Cited by 129 publications

(143 citation statements)

References 55 publications

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“…For clinical validation, we narrowed down the number of genes to three, LHX2, WT1 and OTP, through step-wise selection procedure (described in the results section in this study) which demonstrated a higher level and frequency of methylation in these 3 genes in breast tumor tissue when compared to adjacent normal tissue. Notably our finding of LHX2 and WT1, are also present in the previous gene list (10), indicating that an affinity-based CpG methylation microarray with methylated DNA binding domain of MBD2t or MBD2/MBD3L1 complex is a powerful approach for global methylation mapping.…”

Section: Discussionsupporting

confidence: 76%

“…To expand these findings to novel genes in breast cancer, both gene-specific and genomic-level methylation profiling approaches have been performed (6)(7)(8)(9)(10)(11).…”

Section: Discussionmentioning

confidence: 99%

“…To accomplish this they used CpG microarray analysis in conjunction with the methylated CpG island recovery assay (MIRA), which is based on the affinity of a two protein complex (MBD2/ MBD3L1) attached to methylated DNA. Their data highlighted homeobox genes such as THX1, HOXB13 and HNF1B as new potential methylation biomarkers and demonstrated a high frequency of methylation in significant portion of breast cancers (10).…”

Section: Discussionmentioning

confidence: 99%

“…There have been several studies profiling gene methylation at a genomic level or using panels of known genes (6)(7)(8)(9)(10)(11). These studies have attempted to define methylation sites in genes and determine their frequency of methylation in clinical samples, which may lead to their use in molecular diagnostic testing for early detection of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide identification of OTP gene as a novel methylation marker of breast cancer

Kim¹,

Lee

Oh³

et al. 2012

Oncol Rep

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Abstract. Aberrant DNA methylation occurs early and frequently in tumorigenesis. Identification of DNA methylation biomarkers is a field that provides potential for improving the clinical process of breast cancer diagnosis. We utilized a genome-wide technique, methylated DNA isolation assay (MeDIA), in combination with high-resolution CpG microarray analysis to identify hypermethylated genes in breast cancer. Among differentially methylated genes between tumor and adjacent normal tissues, 3 candidate genes (LHX2, WT1 and OTP) were finally selected through a step-wise filtering process and examined for methylation status in normal tissues, primary tumor, and paired adjacent normal-appearing tissues from 39 breast cancer patients. Based on the calculated cut-off values, all genes showed significantly higher frequencies of aberrant hypermethylation in primary tumors (43.6% for LHX2, 89.7% for WT1 and 100% for OTP, P<0.05) while frequencies were intermediate in paired adjacent normal tissues and absent in normal tissues. On further analysis, the methylation level in primary tumors was not significantly correlated with clinicopathological features. Interestingly, DNA methylation of a novel gene OTP was detected in adjacent normal tissues even 6 cm away from primary tumors, suggesting that OTP methylation may qualify as a biomarker for the early detection of breast cancer. In conclusion, we successfully identified a novel gene OTP frequently methylated in breast cancer by genomewide screening. Our results suggest that the OTP gene may play a crucial role in breast carcinogenesis, although further clinical validation will be needed to evaluate the potential application of OTP in the early detection of breast cancer.

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Section: Discussionsupporting

confidence: 76%

“…To expand these findings to novel genes in breast cancer, both gene-specific and genomic-level methylation profiling approaches have been performed (6)(7)(8)(9)(10)(11).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genome-wide identification of OTP gene as a novel methylation marker of breast cancer

Kim¹,

Lee

Oh³

et al. 2012

Oncol Rep

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“…Recent data showed that the presence of tumor-associated alterations (such as promoter hypermethylation) have been described in the plasma DNA from patients with various kinds of cancer (Kawakami et al, 2000;Duffy et al, 2009). DNA methylation may provide a new generation of cancer biomarkers in the next decade (Duffy et al, 2009;Tommasi et al, 2009). However, no studies have looked into the relationship between the IRX1 molecular marker and gastric cancer.…”

Section: Irx1 Gene In Gastric Carcinomamentioning

confidence: 99%

Homeobox gene IRX1 is a tumor suppressor gene in gastric carcinoma

et al. 2010

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The IRX1 tumor suppressor gene is located on 5p15.33, a cancer susceptibility locus. Loss of heterozygosity of 5p15.33 in gastric cancer was identified in our previous work. In this study, we analyzed the molecular features and function of IRX1. We found that IRX1 expression was lost or reduced in gastric cancer. However, no mutations were identified in IRX1-encoding regions. IRX1 transcription was suppressed by hypermethylation, and the expression of IRX1 mRNA was partially restored in gastric cancer cells after 5-Aza-dC treatment. Restoring IRX1 expression in SGC-7901 and NCI-N87 gastric cancer cells inhibited growth, invasion and tumorigenesis in vitro and in vivo. We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay. BDKRB2, an angiogenesis-related gene, HIST2H2BE and FGF7, cell proliferation and invasionrelated genes, were identified as direct IRX1 target genes. The hypermethylation of IRX1 was not only detected in primary gastric cancer tissues but also in the peripheral blood of gastric cancer patients, suggesting IRX1 could potentially serve as a biomarker for gastric cancer.

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Long noncoding RNA HOXB13‐AS1 regulates HOXB13 gene methylation by interacting with EZH2 in glioma

Xiong

Guo

et al. 2018

Cancer Medicine

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Dysregulation of long noncoding RNAs (lncRNAs) has been implicated in human diseases, in particular, cancers. In this study, we determined the expression of an lncRNA, HOXB13‐AS1, involving in glioma. We showed that HOXB13‐AS1 was significantly upregulated in glioma tissues and cells and was negatively correlated with its surrounding gene HOXB13 levels. Functional experiments in vitro and in vivo revealed that high level of HOXB13‐AS1 increased cell proliferation and tumor growth by promoting cell cycle progression. Conversely, knockdown of HOXB13‐AS1 resulted in decreased cell proliferation and tumor growth. Mechanistically, we showed that HOXB13‐AS1 overexpression increased DNMT3B‐mediated methylation of adjacent gene HOXB13 promoter by binding with the enhancer of zeste homolog 2 (EZH2) using bisulfite sequencing PCR (BSP), epigenetically suppressing HOXB13 expression. Additionally, the interaction between HOXB13‐AS1 and HOXB13 was validated by RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays using antibody against to EZH2. Taken together, our study indicated that HOXB13‐AS1 could regulate HOXB13 gene expression by methylation HOXB13 promoter and acts as an epigenetic oncogenic in glioma.

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Methylation of homeobox genes is a frequent and early epigenetic event in breast cancer

Cited by 129 publications

References 55 publications

Genome-wide identification of OTP gene as a novel methylation marker of breast cancer

Genome-wide identification of OTP gene as a novel methylation marker of breast cancer

Homeobox gene IRX1 is a tumor suppressor gene in gastric carcinoma

Long noncoding RNA HOXB13‐AS1 regulates HOXB13 gene methylation by interacting with EZH2 in glioma

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