DNA methylome combined with chromosome cluster-oriented analysis provides an early signature for cutaneous melanoma aggressiveness
- CNRS-Pierre Fabre, France
- CNRS UMR 7196, INSERM U1154, France
- UMR 1037, INSERM, Université Toulouse III Paul Sabatier, France
- Providence Saint John's Health Center, United States
- Portuguese Oncology Institute, Portugal
- Instituto Europeo di Oncologia, Italy
- Fondation Jean Dausset-CEPH, France
- CNRS, CEA-Institut de Biologie François Jacob, France
- Institut Pasteur, CNRS UMR 3523, France
Abstract
Aberrant DNA methylation is a well‑known feature of tumours and has been associated with metastatic melanoma. However, since melanoma cells are highly heterogeneous, it has been challenging to use affected genes to predict tumour aggressiveness, metastatic evolution, and patients' outcomes. We hypothesized that common aggressive hypermethylation signatures should emerge early in tumorigenesis and should be shared in aggressive cells, independent of the physiological context under which this trait arises. We compared paired melanoma cell lines with the following properties: (i) each pair comprises one aggressive counterpart and its parental cell line, and (ii) the aggressive cell lines were each obtained from different host and their environment (human, rat, and mouse), though starting from the same parent cell line. Next, we developed a multi-step genomic pipeline that combines the DNA methylome profile with a chromosome cluster-oriented analysis. A total of 229 differentially hypermethylated genes were commonly found in the aggressive cell lines. Genome localization analysis revealed hypermethylation peaks and clusters, identifying eight hypermethylated gene promoters for validation in tissues from melanoma patients. Five CpG identified in primary melanoma tissues were transformed into a DNA methylation score that can predict survival (Log-rank test, p=0.0008). This strategy is potentially universally applicable to other diseases involving DNA methylation alterations.
Data availability
Sequencing data have been deposited in GEO under accession code GSE155856R-scripts are available in Source Code 1 fileThe datasets supporting the conclusions of this article are included within the article and the following Supplementary files
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Funding
CNRS (ATIP to PBA)
- Paola B Arimondo
Region Midi Pyrenees-CNRS (Equipe d'excellence to PBA)
- Paola B Arimondo
Region Midi Pyrenees - CNRS (FEDER to PBA)
- Paola B Arimondo
Fondation InnaBioSante (EpAM to PBA)
- Paola B Arimondo
Adelson Medical Research Foundation (grant to DH and MB)
- Dave SB Hoon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Tumour samples from melanoma patients were obtained from the tumour tissue bank at the Department of Pathology, IUCT-O Toulouse Hospital (France). The study was carried out in accordance with the institutional review board-approved protocols (CRB, AC-2013-1955) and the procedures followed were in accordance with the Helsinki Declaration.This study was approved by the institutional ethics committee of IPO Porto (CES-IPOP-FG13/2016).
Copyright
© 2022, Carrier et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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DNA methylome combined with chromosome cluster-oriented analysis provides an early signature for cutaneous melanoma aggressiveness
eLife 11:e78587.
https://doi.org/10.7554/eLife.78587
