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Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):12238-12243. Epub 2016 Oct 10.

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

Author information

1
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.
2
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
3
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
4
Internal Medicine & Oncology, Yale University School of Medicine, New Haven, CT 06510.
5
"Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
6
Department of Pathology, University of Brescia, 25100 Brescia, Italy.
7
Division of Gynecologic Oncology, Universita' Campus Bio-Medico di Roma, 00128 Rome, Italy.
8
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205.
9
Division of Gynecologic Oncology, John Muir Health Clinical Research Center, Concord, CA 94598.
10
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea.
11
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
12
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; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065 richard.lifton@yale.edu.

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.

KEYWORDS:

exome sequencing; ovarian carcinosarcoma; uterine carcinosarcoma

PMID:
27791010
PMCID:
PMC5087050
DOI:
10.1073/pnas.1614120113
[Indexed for MEDLINE]
Free PMC Article

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