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

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 A. Diaz, Christoph Lengauer () and Victor E. Velculescu ()
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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
Christoph Lengauer: Blueprint Medicines
Victor E. Velculescu: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-7

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6006

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