Oncotarget

Research Papers:

NELL1, whose high expression correlates with negative outcomes, has different methylation patterns in alveolar and embryonal rhabdomyosarcoma

Lucia Tombolan _, Elena Poli, Paolo Martini, Angelica Zin, Chiara Romualdi, Gianni Bisogno and Gerolamo Lanfranchi

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Oncotarget. 2017; 8:33086-33099. https://doi.org/10.18632/oncotarget.16526

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Abstract

Lucia Tombolan1,4, Elena Poli4, Paolo Martini1, Angelica Zin3, Chiara Romualdi1, Gianni Bisogno4, Gerolamo Lanfranchi1,2

1Department of Biology, University of Padova, Padova, Italy

2Centro di Ricerca Interdipartimentale per le Biotecnologie Innovative, University of Padova, Padova, Italy

3Institute of Pediatric Research, Padova, Italy

4Department of Women’s and Children’s Health, Oncology Hematology Division, University of Padova, Padova, Italy

Correspondence to:

Lucia Tombolan, email: lucia.tombolan@unipd.it

Keywords: DNA methylation, RRBS, sequencing, rhabdomyosarcoma, NELL1

Received: October 20, 2016     Accepted: March 14, 2017     Published: March 23, 2017

ABSTRACT

Rhabdomyosarcoma (RMS), which represents the most frequent soft tissue sarcoma in pediatric populations, is classified into two major subtypes: embryonal RMS (ERMS) and alveolar RMS (ARMS). ARMS subtype, which shows greater aggressiveness and proneness to metastasis with respect to ERMS, are characterized, in about 75% of cases, by specific chromosomal translocations that involve PAX and FOXO1 genes. Many findings have demonstrated that PAX/FOXO1-positive ARMS have a worse prognosis than PAX/FOXO1-negative ones and that distinct molecular features characterize RMS with different gene fusion statuses. DNA methylation, which presently represents a challenging research area, is involved in the modulation of gene expression.

We performed a genome-wide DNA methylation analysis using reduced-representation bisulfite sequencing (RRBS) in RMS samples and we found that fusion-positive alveolar and embryonal subgroups have different DNA methylation signatures and that ARMS fusion-positive subtypes are characterized by overall hypomethylation levels. While NELL1 was found to be hypomethylated and transcriptionally enhanced in RMS alveolar subtypes, high NELL1 expression levels, which proved to be correlated with negative RMS prognostic factors such as fusion status and histology (P < 0.0001), were found to discriminate between RMS patients with different outcomes (P < 0.05).

In conclusion, our results demonstrated that different DNA methylation patterns distinguish between different RMS subgroups and they suggest that epigenetic signatures could be useful for risk stratification of patients.


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