Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition

• DOI: 10.1073/pnas.1614120113
• Publication Date: 2016-10-11T17:24:07Z
• Authors: Siming Zhao; Stefania Bellone; Salvatore Lopez; Durga Thakral; Carlton Schwab; Diana P. English; Jonathan Black; Emiliano Cocco; Jungmin Choi; Luca Zammataro; Federica Predolini; Elena Bonazzoli; Mark Bi; Natalia Buza; Pei Hui; Serena Wong; Maysa Abu-Khalaf; Antonella Ravaggi; Eliana Bignotti; Elisabetta Bandiera; Chiara Romani; Paola Todeschini; Renata Tassi; Laura Zanotti; Franco Odicino; Sergio Pecorelli; Carla Donzelli; Laura Ardighieri; Fabio Facchetti; Marcella Falchetti; Dan-Arin Silasi; Elena Ratner; Masoud Azodi; Peter E. Schwartz; Shrikant Mane; Roberto Angioli; Corrado Terranova; Charles Matthew Q...; Babak Edraki; Kaya Bilgüvar; Moses Lee; Murim Choi; Amy L. Stiegler; Titus J. Boggon; Joseph Schlessinger; Richard P. Lifton; Alessandro D. Santin
• Keywords: Aged, 80 and over; Ovarian Neoplasms; Epithelial-Mesenchymal Transition; Class I Phosphatidylinositol 3-Kinases; PTEN Phosphohydrolase; Exome sequencing; Ovarian carcinosarcoma; Uterine carcinosarcoma; Multidisciplinary; Middle Aged; 3. Good health; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Histones; 03 medical and health sciences; 0302 clinical medicine; Carcinosarcoma; Mutation; Uterine Neoplasms; Humans; Female; Tumor Suppressor Protein p53; Telomerase; Aged

Significance Some cancers, termed carcinosarcomas (CSs), have mixed cell types, with either epithelial or mesenchymal features. Sequencing the genomes of uterine and ovarian CSs demonstrated that these different cell types derive from a common precursor cell that has many mutations typical of epithelial cancers. In addition, we find that these tumors have a significant burden of point mutations and amplification of histone genes, suggesting a potential role of these mutations in sarcomatous transformation. Consistent with this finding, expression of specific histone gene mutations in uterine carcinoma cells changed gene expression toward a mesenchymal state. These findings have potential implications for the treatment of these cancers.