title: Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition.
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.
authors: 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.
authors: Siming
authors: S
authors: Zhao
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Stefania
authors: S
authors: Bellone
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Salvatore
authors: S
authors: Lopez
authors: 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.
authors: Durga
authors: D
authors: Thakral
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Carlton
authors: C
authors: Schwab
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Diana P
authors: DP
authors: English
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Jonathan
authors: J
authors: Black
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Emiliano
authors: E
authors: Cocco
authors: 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.
authors: Jungmin
authors: J
authors: Choi
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Luca
authors: L
authors: Zammataro
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Federica
authors: F
authors: Predolini
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Elena
authors: E
authors: Bonazzoli
authors: 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.
authors: Mark
authors: M
authors: Bi
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
authors: Natalia
authors: N
authors: Buza
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
authors: Pei
authors: P
authors: Hui
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
authors: Serena
authors: S
authors: Wong
authors: Internal Medicine & Oncology, Yale University School of Medicine, New Haven, CT 06510.
authors: Maysa
authors: M
authors: Abu-Khalaf
authors: "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
authors: Antonella
authors: A
authors: Ravaggi
authors: "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
authors: Eliana
authors: E
authors: Bignotti
authors: "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
authors: Elisabetta
authors: E
authors: Bandiera
authors: "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
authors: Chiara
authors: C
authors: Romani
authors: "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
authors: Paola
authors: P
authors: Todeschini
authors: "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
authors: Renata
authors: R
authors: Tassi
authors: "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
authors: Laura
authors: L
authors: Zanotti
authors: "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
authors: Franco
authors: F
authors: Odicino
authors: "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics & Gynecology, University of Brescia, 25100 Brescia, Italy.
authors: Sergio
authors: S
authors: Pecorelli
authors: Department of Pathology, University of Brescia, 25100 Brescia, Italy.
authors: Carla
authors: C
authors: Donzelli
authors: Department of Pathology, University of Brescia, 25100 Brescia, Italy.
authors: Laura
authors: L
authors: Ardighieri
authors: Department of Pathology, University of Brescia, 25100 Brescia, Italy.
authors: Fabio
authors: F
authors: Facchetti
authors: Department of Pathology, University of Brescia, 25100 Brescia, Italy.
authors: Marcella
authors: M
authors: Falchetti
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Dan-Arin
authors: DA
authors: Silasi
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Elena
authors: E
authors: Ratner
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Masoud
authors: M
authors: Azodi
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Peter E
authors: PE
authors: Schwartz
authors: 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.
authors: Shrikant
authors: S
authors: Mane
authors: Division of Gynecologic Oncology, Universita' Campus Bio-Medico di Roma, 00128 Rome, Italy.
authors: Roberto
authors: R
authors: Angioli
authors: Division of Gynecologic Oncology, Universita' Campus Bio-Medico di Roma, 00128 Rome, Italy.
authors: Corrado
authors: C
authors: Terranova
authors: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205.
authors: Charles Matthew
authors: CM
authors: Quick
authors: Division of Gynecologic Oncology, John Muir Health Clinical Research Center, Concord, CA 94598.
authors: Babak
authors: B
authors: Edraki
authors: 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.
authors: Kaya
authors: K
authors: Bilgüvar
authors: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors: Moses
authors: M
authors: Lee
authors: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors: Murim
authors: M
authors: Choi
authors: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
authors: Amy L
authors: AL
authors: Stiegler
authors: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
authors: Titus J
authors: TJ
authors: Boggon
authors: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
authors: Joseph
authors: J
authors: Schlessinger
authors: 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.
authors: Richard P
authors: RP
authors: Lifton
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
authors: Alessandro D
authors: AD
authors: Santin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002296:Carcinosarcoma / Q000235:genetics / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C115369:MBD3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C509186:TERT protein, human; D019098:Telomerase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: exome sequencing; ovarian carcinosarcoma; uterine carcinosarcoma