Integrated DNA methylation analysis identifies topographical and tumoral biomarkers in pilocytic astrocytomas

Antonelli, Manila; Fadda, Antonio; Loi, Eleonora; Moi, Loredana; Zavattari, Cesare; Sulas, Pia; Gentilini, Davide; Cameli, Cinzia; Bacchelli, Elena; Badiali, Manuela; Arcella, Antonella; Morra, Isabella; Giangaspero, Felice; Zavattari, Patrizia

doi:10.18632/oncotarget.24480

Cited by 18 publications

(14 citation statements)

References 42 publications

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“…These results confirmed the association between promoter hypermethylation and gene downregulation already reported, considering methylation as a mechanism for gene transcriptional inactivation in cancer [34,35]. Moreover, the expression levels of most of the genes studied in this work, were already low in colon normal tissues (GTEx data, https://www.gtexportal.org) supporting the idea that methylation in cancer targets genes barely expressed in tissues where tumour arises [4,[36][37][38]. Interestingly, our study shows that these genes are further repressed in tumour tissues that can be observed only by means of a targeted gene expression analysis as previously reported [4,36,39].…”

Section: Discussionsupporting

confidence: 91%

Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression

Vega-Benedetti

Loi

Moi

et al. 2020

IJMS

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Colorectal cancer (CRC) is a major cause of cancer mortality. Early diagnosis is relevant for its prevention and treatment. Since DNA methylation alterations are early events in tumourigenesis and can be detected in cell-free DNA, they represent promising biomarkers for early CRC diagnosis through non-invasive methods. In our previous work, we identified 74 early altered CpG islands (CGIs) associated with genes involved in cell cross-talking and cell signalling pathways. The aim of this work was to test whether methylation-based biomarkers could be detected in non-invasive matrices. Our results confirmed methylation alterations of GRIA4 and VIPR2 in CRC tissues, using MethyLight, as well as in stool samples, using a much more sensitive technique as droplet digital PCR. Furthermore, we analysed expression levels of selected genes whose promoter CGIs were hypermethylated in CRC, detecting downregulation at mRNA and protein levels in CRC tissue for GRIA4, VIPR2, SPOCK1 and SLC6A3. Most of these genes were already lowly expressed in colon normal tissues supporting the idea that cancer DNA methylation targets genes already barely expressed in the matched normal tissues. Our study suggests GRIA4 and VIPR2 as biomarkers for early CRC diagnosis using stool samples and confirms downregulation of genes hypermethylated in CRC.

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Section: Discussionsupporting

confidence: 91%

Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression

Vega-Benedetti

Loi

Moi

et al. 2020

IJMS

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“…returning to the conditions required during development. However, it should also be considered the possibility that the methylation status found in the tumour actually mirrors the cell of origin pattern clonally expanded [24, 40, 46–48]. In this case, it may not represent a cause or an effect of tumorigenesis, but still a cancer-specific clustered PCDH methylation pattern would remain a valuable biomarker.…”

Section: Discussionmentioning

confidence: 99%

“…The number of probes mapping in PCDHG @ cluster in the different BeadChips are reported in Additional file 1: Figure S1. Further information and clinical data are available in Antonelli et al (PA study) and Fadda et al (CRC study) [24, 25].…”

Section: Methodsmentioning

confidence: 99%

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Clustered protocadherins methylation alterations in cancer

et al. 2019

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Background Clustered protocadherins ( PCDHs ) map in tandem at human chromosome 5q31 and comprise three multi-genes clusters: α-, β- and γ- PCDH . The expression of this cluster consists of a complex mechanism involving DNA hub formation through DNA-CCTC binding factor (CTCF) interaction. Methylation alterations can affect this interaction, leading to transcriptional dysregulation. In cancer, clustered PCDH s undergo a mechanism of long-range epigenetic silencing by hypermethylation. Results In this study, we detected frequent methylation alterations at CpG islands associated to these clustered PCDHs in all the solid tumours analysed (colorectal, gastric and biliary tract cancers, pilocytic astrocytoma), but not hematologic neoplasms such as chronic lymphocytic leukemia. Importantly, several altered CpG islands were associated with CTCF binding sites. Interestingly, our analysis revealed a hypomethylation event in pilocytic astrocytoma, suggesting that in neuronal tissue, where PCDH s are highly expressed, these genes become hypomethylated in this type of cancer. On the other hand, in tissues where PCDH s are lowly expressed, these CpG islands are targeted by DNA methylation. In fact, PCDH -associated CpG islands resulted hypermethylated in gastrointestinal tumours. Conclusions Our study highlighted a strong alteration of the clustered PCDHs methylation pattern in the analysed solid cancers and suggested these methylation aberrations in the CpG islands associated with PCDH genes as powerful diagnostic biomarkers. Electronic supplementary material The online version of this article (10.1186/s13148-019-0695-0) contains supplementary material, which is available to authorized users.

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“…Nevertheless, the consistency of spatio-temporal localization of even this small set of genes across multiple datasets partially mitigates this limitation. Moreover, several PA-DR genes, most notably Pax3 and the members of the Iroquois family (Irx5 and Irx2), have consistently been reported to be differentially methylated [25,51,52] and expressed at both the mRNA [25,45,51,53] and protein levels [53] in infratentorial tumors, strengthening the selection of genes used in this study.…”

Section: Plos Onementioning

confidence: 52%

In silico analysis identifies a putative cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma

Younes

Herrington

2020

PLoS ONE

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Childhood cancers are increasingly recognized as disorders of cellular development. This study sought to identify the cellular and developmental origins of cerebellar pilocytic astrocytoma, the most common brain tumor of childhood. Using publicly available gene expression data from pilocytic astrocytoma tumors and controlling for driver mutation, a set of developmental-related genes which were overexpressed in cerebellar pilocytic astrocytoma was identified. These genes were then mapped onto several developmental atlases in order to identify normal cells with similar gene expression patterns and the developmental trajectory of those cells was interrogated. Eight known neuro-developmental genes were identified as being expressed in cerebellar pilocytic astrocytoma. Mapping those genes or their orthologs onto mouse neuro-developmental atlases identified overlap in their expression within the ventricular zone of the cerebellar anlage. Further analysis with a single cell RNA-sequencing atlas of the developing mouse cerebellum defined this overlap as occurring in ventricular zone progenitor cells at the division point between GABA-ergic neuronal and glial lineages, a developmental trajectory which closely mirrors that previously described to occur within pilocytic astrocytoma cells. Furthermore, ventricular zone progenitor cells and their progeny exhibited evidence of MAPK pathway activation, the paradigmatic oncogenic cascade known to be active in cerebellar pilocytic astrocytoma. Gene expression from developing human brain atlases recapitulated the same anatomic localizations and developmental trajectories as those found in mice. Taken together, these data suggest this population of ventricular zone progenitor cells as the cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma.

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Integrated DNA methylation analysis identifies topographical and tumoral biomarkers in pilocytic astrocytomas

Cited by 18 publications

References 42 publications

Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression

Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression

Clustered protocadherins methylation alterations in cancer

In silico analysis identifies a putative cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma

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