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Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas

Clinical Cancer Research, ISSN: 1557-3265, Vol: 22, Issue: 9, Page: 2301-2310
2016
  • 115
    Citations
  • 0
    Usage
  • 87
    Captures
  • 2
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    115
    • Citation Indexes
      113
    • Clinical Citations
      1
      • PubMed Guidelines
        1
    • Policy Citations
      1
      • Policy Citation
        1
  • Captures
    87
  • Mentions
    2
    • News Mentions
      1
      • News
        1
    • References
      1
      • Wikipedia
        1

Most Recent News

Therapies Targeting the Signal Pathways of Pheochromocytoma and Paraganglioma

Abstract:Pheochromocytoma and paraganglioma (PCC/PGL) are rare tumors that originate from adrenal or extra-adrenal chromaffin cells. A significant clinical manifestation of PCC/PGL is that the tumors

Article Description

Purpose: Pheochromocytomas and paragangliomas (PPGL) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown. Experimental Design: We performed exome or transcriptome sequencing of 43 samples from 41 patients. A validation set of 136 PPGLs was used for amplicon-specific resequencing. In addition, a subset of these tumors was subjected to microarray-based transcription, protein expression, and histone methylation analysis by Western blotting or immunohistochemistry. In vitro analysis of mutants was performed in cell lines. Results: We detected mutations in chromatin-remodeling genes, including histone-methyltransferases, histone-demethylases, and histones in 11 samples from 8 patients (20%). In particular, we characterized a new cancer syndrome involving PPGLs and giant cell tumors of bone (GCT) caused by a postzygotic G34W mutation of the histone 3.3 gene, H3F3A. Furthermore, mutations in kinase genes were detected in samples from 15 patients (37%). Among those, a novel germline kinase domain mutation of MERTK detected in a patient with PPGL and medullary thyroid carcinoma was found to activate signaling downstream of this receptor. Recurrent germline and somatic mutations were also detected in MET, including a familial case and sporadic PPGLs. Importantly, in each of these three genes, mutations were also detected in the validation group. In addition, a somatic oncogenic hotspot FGFR1 mutation was found in a sporadic tumor. Conclusions: This study implicates chromatin-remodeling and kinase variants as frequent genetic events in PPGLs, many of which have no other known germline driver mutation. MERTK, MET, and H3F3A emerge as novel PPGL susceptibility genes.

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