HOXA7, 9, and 10 are methylation targets associated with aggressive behavior in meningiomas

Vinci, Angela Di; Brigati, Claudio; Casciano, Ida; Banelli, Barbara; Borzì, Luana; Forlani, Alessandra; Ravetti, Gian Luigi; Allemanni, Giorgio; Melloni, Ilaria; Zona, Gianluigi; Spaziante, Renato; Merlo, Domenico Franco; Romani, Massimo

doi:10.1016/j.trsl.2012.05.007

Cited by 35 publications

(26 citation statements)

References 27 publications

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“…None of these genes were selected by our meningioma predictor model although in some instances members of the same gene family were present in our gene list (solute carrier proteins, paired box, and forkhead box transcription factors). It is interesting to notice that hypermethylation of HOXA11, HOXA6 , and HOXA9 were reported in aggressive meningiomas by several studies [35,21,15] but our analysis did not identify these genes as important predictors of outcome. However, on manual inspection of all unfiltered CpG loci located on HOXA11, HOXA6 , and HOXA9, there were significant differences with increased levels of methylation in the MM-UNFAV group compared to MM-FAV group (findings limited to the validation dataset) (Online resource 9) confirming the findings in the literature.…”

Section: Discussioncontrasting

confidence: 64%

“…In the past, several studies focused on investigating promoter methylation mainly using a targeted approach for a limited number of genes [4,6–8,11,30,14,15,34,38,47]. With time, molecular advances allowed interrogation at a larger number of CpG loci [35] culminating with the methylation assays from Illumina (27k and 450k) interrogating approximately 27.000 and 450.000 CpG loci [74,21].…”

Section: Discussionmentioning

confidence: 99%

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Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Olar

Wani

Wilson³

et al. 2017

Acta Neuropathol

154

118

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Meningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n=140) were profiled using the Illumina HumanMethylation450 BeadChip. Unsupervised modeling on a training set (n=89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence free survival (RFS) times between the groups: a prognostically unfavorable subgroup (MM-UNFAV) and a prognostically favorable subgroup (MM-FAV). This finding was validated in the remaining 51 samples and led to a baseline meningioma methylation classifier (bMMC) defined by 283 CpG loci (283-bMMC). To further optimize a recurrence predictor, probes subsumed within the baseline classifier were subject to additional modeling using a similar training/validation approach, leading to a 64-CpG loci meningioma methylation predictor (64-MMP). After adjustment for relevant clinical variables [WHO grade, mitotic index, Simpson grade, sex, location, and copy number aberrations (CNA)] multivariable analyses for RFS showed that the baseline methylation classifier was not significant (p=0.0793). The methylation predictor however was significantly associated with tumor recurrence (p<0.0001). CNA were extracted from the 450k intensity profiles. Tumor samples in the MM-UNFAV subgroup showed an overall higher proportion of CNAs compared to the MM-FAV subgroup tumors and the CNAs were complex in nature. CNAs in the MM-UNFAV subgroup included recurrent losses of 1p, 6q, 14q and 18q, and gain of 1q, all of which were previously identified as indicators of poor outcome. In conclusion, our analyses demonstrate robust DNA methylation signatures in meningioma that correlate with CNAs and stratify patients by recurrence risk.

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Section: Discussioncontrasting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Olar

Wani

Wilson³

et al. 2017

Acta Neuropathol

154

118

View full text Add to dashboard Cite

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“…All of these five genes can act as transcription factors to affect early embryo development. For instances, Dmrta2 in mice is essential in the early development of the telencephalon via the formation of the cortical hem and maintaining of neural progenitors [39]; homeobox genes HOXA9 and HOXA7 spatially and temporally regulate morphogenesis and differentiation during embryonic development [40]; homeobox gene SIX3 provides necessary instructions for the formation of the forebrain and eye development [41]; ZIC4 has been proposed to regulate lateemerging characteristics in the dorsal surface with ZIC1 [42]. Due to their important roles in embryo development, methylation of these genes could affect important cellular functions and eventually promote tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Selection of Sensitive Methylation Markers for the Detection of Non-small Cell Lung Cancer

Zhao¹,

Jen²,

Peikert³

2015

J Mol Biomark Diagn

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“…Additionally, focal DNA hypermethylation at regional hotspots (including CpG islands) was observed in different human tumors [20], [21], [22], [23]. DNA methylation levels of HOXA7 , HOXA9 and HOXA10 were reported significantly higher in WHO grade II and III meningiomas [24] than in grade I (benign) meningiomas. DNA methylation of a group of 6,157 genes was previously studied to identify biomarkers correlated with a high frequency of tumor recurrence in WHO grade I and II meningiomas [25].…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation in the Malignant Transformation of Meningiomas

et al. 2013

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Meningiomas are central nervous system tumors that originate from the meningeal coverings of the brain and spinal cord. Most meningiomas are pathologically benign or atypical, but 3–5% display malignant features. Despite previous studies on benign and atypical meningiomas, the key molecular pathways involved in malignant transformation remain to be determined, as does the extent of epigenetic alteration in malignant meningiomas. In this study, we explored the landscape of DNA methylation in ten benign, five atypical and four malignant meningiomas. Compared to the benign tumors, the atypical and malignant meningiomas demonstrate increased global DNA hypomethylation. Clustering analysis readily separates malignant from atypical and benign tumors, implicating that DNA methylation patterns may serve as diagnostic biomarkers for malignancy. Genes with hypermethylated CpG islands in malignant meningiomas (such as HOXA6 and HOXA9) tend to coincide with the binding sites of polycomb repressive complexes (PRC) in early developmental stages. Most genes with hypermethylated CpG islands at promoters are suppressed in malignant and benign meningiomas, suggesting the switching of gene silencing machinery from PRC binding to DNA methylation in malignant meningiomas. One exception is the MAL2 gene that is highly expressed in benign group and silenced in malignant group, representing de novo gene silencing induced by DNA methylation. In summary, our results suggest that malignant meningiomas have distinct DNA methylation patterns compared to their benign and atypical counterparts, and that the differentially methylated genes may serve as diagnostic biomarkers or candidate causal genes for malignant transformation.

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HOXA7, 9, and 10 are methylation targets associated with aggressive behavior in meningiomas

Cited by 35 publications

References 27 publications

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

Selection of Sensitive Methylation Markers for the Detection of Non-small Cell Lung Cancer

DNA Methylation in the Malignant Transformation of Meningiomas

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