Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncomms7044
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Funding
- La Ligue Nationale contre le Cancer
- CIT Program
- Genetics Department and Biological Resources Center and Tumor Bank Platform, Hopital europeen Georges Pompidou [BB-0033-00063]
- Agence Nationale de la Recherche [ANR 08 GENOPATH 029 MitOxy, ANR-2011-JCJC-00701 MODEOMAPP]
- Programme Hospitalier de Recherche Clinique grant COMETE 3 [AOM 06 179]
- Plan Cancer : Appel projets Epigntique et Cancer [EPIG201303 METABEPIC]
- European Union Seventh Framework Program (FP7) [259735]
- La Fondation ARC [DOC20130606831]
- Cancer Research for Personalized Medicine-CARPEM project (Site de Recherche Integre sur le Cancer-SIRIC)
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Pheochromocytomas and paragangliomas (PCCs/PGLs) are neural crest-derived tumours with a very strong genetic component. Here we report the first integrated genomic examination of a large collection of PCC/PGL. SNP array analysis reveals distinct copy-number patterns associated with genetic background. Whole-exome sequencing shows a low mutation rate of 0.3 mutations per megabase, with few recurrent somatic mutations in genes not previously associated with PCC/PGL. DNA methylation arrays and miRNA sequencing identify DNA methylation changes and miRNA expression clusters strongly associated with messenger RNA expression profiling. Overexpression of the miRNA cluster 182/96/183 is specific in SDHB-mutated tumours and induces malignant traits, whereas silencing of the imprinted DLK1-MEG3 miRNA cluster appears as a potential driver in a subgroup of sporadic tumours. Altogether, the complete genomic landscape of PCC/PGL is mainly driven by distinct germline and/or somatic mutations in susceptibility genes and reveals different molecular entities, characterized by a set of unique genomic alterations.
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