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

Siming Zhao, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
Stefania Bellone, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Salvatore Lopez, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Durga Thakral, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
Carlton Schwab, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Diana P. English, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Jonathan Black, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Emiliano Cocco, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Jungmin Choi, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
Luca Zammataro, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Federica Predolini, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Elena Bonazzoli, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Mark Bi, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
Natalia Buza, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Pei Hui, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Serena Wong, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Maysa Abu-Khalaf, Internal Medicine & Oncology, Yale University School of Medicine, New Haven, CT 06510.
Antonella Ravaggi, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
Eliana Bignotti, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
Elisabetta Bandiera, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
Chiara Romani, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
Paola Todeschini, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
Renata Tassi, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
Laura Zanotti, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
Franco Odicino, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
Sergio Pecorelli, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
Carla Donzelli, Department of Pathology, University of Brescia, 25100 Brescia, Italy.
Laura Ardighieri, Department of Pathology, University of Brescia, 25100 Brescia, Italy.
Fabio Facchetti, Department of Pathology, University of Brescia, 25100 Brescia, Italy.
Marcella Falchetti, Department of Pathology, University of Brescia, 25100 Brescia, Italy.
Dan-Arin Silasi, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Elena Ratner, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.

Document Type

Article

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

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.

First Page

12238

Last Page

12243

DOI

10.1073/pnas.1614120113

Publication Date

10-25-2016

Identifier

27791010 (pubmed); PMC5087050 (pmc); 10.1073/pnas.1614120113 (doi); 1614120113 (pii)

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