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Abstract LB-87: A novel epigenetic blood test to monitor minimal residual disease in high-risk neuroblastoma.

Petrie, Kevin, Field, Megan, Ahmad, Zai, Dezfouli, Mehrnoush, Barker, Karen, Jeznach, Magdalena, Glass, Laura, Hallsworth, Albert, Sbirkov, Yordan, Womersley, Howard, Zelent, Arthur, Jordan, Philip, Akoulitchev, Alexandre and Chesler, Louis (2013) Abstract LB-87: A novel epigenetic blood test to monitor minimal residual disease in high-risk neuroblastoma. Cancer Research, 73 (8_Supp). LB-87. ISSN 0008-5472

Item Type: Article

Abstract

Background: Cells present as minimal residual disease (MRD) following frontline therapy drive chemoresistant tumour relapse, thus their detection and targeting is a major priority in cancer therapy. Neuroblastoma (NB) is an aggressive neural crest-derived malignancy of infants and young children. A hallmark of NB is its clinical heterogeneity and the majority of infants with NB have a unique biology that results in spontaneous remission through differentiation in the absence of therapy, despite disease that may be disseminated to the liver, skin, and bone marrow at diagnosis. These infants (with stage 4S disease) have survival rates that exceed 95%. Children with high-risk NB, however, largely characterized by amplification of the MYCN oncogene, often have a disease that is therapy resistant. Although modest improvements in outcome have been achieved as a result of therapy intensification, 5-year event free survival in high-risk patients remains approximately 40-50%. Typically, high-risk neuroblastoma recurs after near complete remission is achieved and the development of effective strategies directed at MRD remains an unmet clinical need.
Detection of MRD in neuroblastoma is usually performed using real-time quantitative (RQ)-PCR of neuroblastoma-specific transcripts. Tumor-selective mRNA markers levels are highly dependent on gene expression, which can vary between patients (by a factor of up 1000) and change during treatment. Furthermore, the applicability of a PCR target for MRD detection is also determined by its background expression in hematologic cells. Chromatin conformation patterns integrate the spatial arrangement of the chromatin and build a signature for the physiological status of the cell representing early changes in the genetic and epigenetic regulation. These signatures form the basis for a new technology, Episwitch™, which can identify epigenetic patterns linked with cancer progression and aggressiveness.
Results: Based on a screen of human NB cell lines containing amplification of MYCN or expression of high levels of MYCN protein versus NB cell lines lacking expression of MYCN, we have identified a panel of four NB-associated genetic markers: HDM2, PHOX2B, TERT and TH. HDM2 and TERT are direct transcriptional targets of MYCN. This epigenetic signature is currently being validated in primary NB samples. An in vivo proof of concept study utilizing the equivalent mouse epigenetic signature is being performed in a relapse model of MYCN-driven NB.
Conclusion: In this study we have developed and tested a novel blood test based on Episwitch™ technology that discriminates MYCN-associated NB. Our data suggest this non-invasive test can be used to monitor remission/relapse status quantitatively with high sensitivity in high-risk MYCN-associated neuroblastoma, thus informing treatment decisions.

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More Information

Depositing User: Kevin Petrie

Identifiers

Item ID: 15821
Identification Number: https://doi.org/10.1158/1538-7445.am2013-lb-87
ISSN: 0008-5472
URI: http://sure.sunderland.ac.uk/id/eprint/15821
Official URL: http://dx.doi.org/10.1158/1538-7445.am2013-lb-87

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 22 Mar 2023 15:46
Last Modified: 22 Mar 2023 15:46

Contributors

Author: Kevin Petrie ORCID iD
Author: Megan Field
Author: Zai Ahmad
Author: Mehrnoush Dezfouli
Author: Karen Barker
Author: Magdalena Jeznach
Author: Laura Glass
Author: Albert Hallsworth
Author: Yordan Sbirkov
Author: Howard Womersley
Author: Arthur Zelent
Author: Philip Jordan
Author: Alexandre Akoulitchev
Author: Louis Chesler

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences

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