title: Uterine adenosarcomas are mesenchymal neoplasms.
abstract: Uterine adenosarcomas (UAs) are biphasic lesions composed of a malignant mesenchymal (ie stromal) component and an epithelial component. UAs are generally low-grade and have a favourable prognosis, but may display sarcomatous overgrowth (SO), which is associated with a worse outcome. We hypothesized that, akin to breast fibroepithelial lesions, UAs are mesenchymal neoplasms in which clonal somatic genetic alterations are restricted to the mesenchymal component. To characterize the somatic genetic alterations in UAs and to test this hypothesis, we subjected 20 UAs to a combination of whole-exome (n = 6), targeted capture (n = 13) massively parallel sequencing (MPS) and/or RNA sequencing (n = 6). Only three genes, FGFR2, KMT2C and DICER1, were recurrently mutated, all in 2/19 cases; however, 26% (5/19) and 21% (4/19) of UAs harboured MDM2/CDK4/HMGA2 and TERT gene amplification, respectively, and two cases harboured fusion genes involving NCOA family members. Using a combination of laser-capture microdissection and in situ techniques, we demonstrated that the somatic genetic alterations detected by MPS were restricted to the mesenchymal component. Furthermore, mitochondrial DNA sequencing of microdissected samples revealed that epithelial and mesenchymal components of UAs were clonally unrelated. In conclusion, here we provide evidence that UAs are genetically heterogeneous lesions and mesenchymal neoplasms.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Burke
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.|Department of Pathology, Patras General Hospital, University of Patras, Greece.
authors.forename: Anastasios D
authors.initials: AD
authors.lastname: Papanastasiou
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.|Department of Pathology, Hospital Israelita Albert Einstein, Instituto Israelita de Ensino e Pesquisa, São Paulo, Brazil.
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Macedo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Luciano G
authors.identifier: http://orcid.org/0000-0002-9625-1183
authors.initials: LG
authors.lastname: Martelotto
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Ino
authors.initials: I
authors.lastname: de Bruijn
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Maria R
authors.initials: MR
authors.lastname: De Filippo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Schultheis
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Ioris
authors.affiliation: Gynaecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
mesh_terms: D018195:Adenosarcoma / Q000235:genetics* / Q000473:pathology; D005260:Female; D050939:Gene Fusion / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017403:In Situ Hybridization; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins
keywords: FISH; RNA sequencing; massively parallel sequencing; uterine adenosarcoma