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Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes

Author

Listed:
  • Siân Jones

    (Personal Genome Diagnostics)

  • Nicolas Stransky

    (Blueprint Medicines)

  • Christine L. McCord

    (Personal Genome Diagnostics)

  • Ethan Cerami

    (Blueprint Medicines)

  • James Lagowski

    (Knight Cancer Institute, Oregon Health and Science University)

  • Devon Kelly

    (Knight Cancer Institute, Oregon Health and Science University)

  • Samuel V. Angiuoli

    (Personal Genome Diagnostics)

  • Mark Sausen

    (Personal Genome Diagnostics)

  • Lisa Kann

    (Personal Genome Diagnostics)

  • Manish Shukla

    (Personal Genome Diagnostics)

  • Rosemary Makar

    (Knight Cancer Institute, Oregon Health and Science University)

  • Laura D. Wood

    (Johns Hopkins University)

  • Luis A. Diaz

    (The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
    Swim Across America Laboratory and the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins)

  • Christoph Lengauer

    (Blueprint Medicines)

  • Victor E. Velculescu

    (The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine)

Abstract

Malignant mixed Müllerian tumours, also known as carcinosarcomas, are rare tumours of gynaecological origin. Here we perform whole-exome analyses of 22 tumours using massively parallel sequencing to determine the mutational landscape of this tumour type. On average, we identify 43 mutations per tumour, excluding four cases with a mutator phenotype that harboured inactivating mutations in mismatch repair genes. In addition to mutations in TP53 and KRAS, we identify genetic alterations in chromatin remodelling genes, ARID1A and ARID1B, in histone methyltransferase MLL3, in histone deacetylase modifier SPOP and in chromatin assembly factor BAZ1A, in nearly two thirds of cases. Alterations in genes with potential clinical utility are observed in more than three quarters of the cases and included members of the PI3-kinase and homologous DNA repair pathways. These findings highlight the importance of the dysregulation of chromatin remodelling in carcinosarcoma tumorigenesis and suggest new avenues for personalized therapy.

Suggested Citation

  • Siân Jones & Nicolas Stransky & Christine L. McCord & Ethan Cerami & James Lagowski & Devon Kelly & Samuel V. Angiuoli & Mark Sausen & Lisa Kann & Manish Shukla & Rosemary Makar & Laura D. Wood & Luis, 2014. "Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes," Nature Communications, Nature, vol. 5(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6006
    DOI: 10.1038/ncomms6006
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