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

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 BandieraChiara 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 Quick, Babak Edraki, Kaya Bilgüvar, Moses Lee, Murim Choi, Amy L. Stiegler, Titus J. Boggon, Joseph Schlessinger, Richard P. Lifton, Alessandro D. Santin

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)

Abstract

Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements.We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC. Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial-mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms.

Original languageEnglish
Pages (from-to)12238-12243
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number43
DOIs
Publication statusPublished - 2016 Oct 25
Externally publishedYes

Keywords

  • Exome sequencing
  • Ovarian carcinosarcoma
  • Uterine carcinosarcoma

ASJC Scopus subject areas

  • General

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