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Leukemia. 2014 May;28(5):1052-9. doi: 10.1038/leu.2013.302. Epub 2013 Oct 22.

Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms.

Author information

1
1] Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy [2] Life Sciences Department, University of Modena and Reggio Emilia, Modena, Italy [3] Center for Regenerative Medicine 'Stefano Ferrari', University of Modena and Reggio Emilia, Modena, Italy.
2
1] Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy [2] Life Sciences Department, University of Modena and Reggio Emilia, Modena, Italy.
3
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
4
1] Life Sciences Department, University of Modena and Reggio Emilia, Modena, Italy [2] Center for Regenerative Medicine 'Stefano Ferrari', University of Modena and Reggio Emilia, Modena, Italy.

Abstract

With the intent of dissecting the molecular complexity of Philadelphia-negative myeloproliferative neoplasms (MPN), we designed a target enrichment panel to explore, using next-generation sequencing (NGS), the mutational status of an extensive list of 2000 cancer-associated genes and microRNAs. The genomic DNA of granulocytes and in vitro-expanded CD3+T-lymphocytes, as a germline control, was target-enriched and sequenced in a learning cohort of 20 MPN patients using Roche 454 technology. We identified 141 genuine somatic mutations, most of which were not previously described. To test the frequency of the identified variants, a larger validation cohort of 189 MPN patients was additionally screened for these mutations using Ion Torrent AmpliSeq NGS. Excluding the genes already described in MPN, for 8 genes (SCRIB, MIR662, BARD1, TCF12, FAT4, DAP3, POLG and NRAS), we demonstrated a mutation frequency between 3 and 8%. We also found that mutations at codon 12 of NRAS (NRASG12V and NRASG12D) were significantly associated, for primary myelofibrosis (PMF), with highest dynamic international prognostic scoring system (DIPSS)-plus score categories. This association was then confirmed in 66 additional PMF patients composing a final dataset of 168 PMF showing a NRAS mutation frequency of 4.7%, which was associated with a worse outcome, as defined by the DIPSS plus score.

PMID:
24150215
PMCID:
PMC4017260
DOI:
10.1038/leu.2013.302
[Indexed for MEDLINE]
Free PMC Article
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