Uterine adenosarcomas are mesenchymal neoplasms

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...

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Published inThe Journal of pathology Vol. 238; no. 3; pp. 381 - 388
Main Authors Piscuoglio, Salvatore, Burke, Kathleen A, Ng, Charlotte KY, Papanastasiou, Anastasios D, Geyer, Felipe C, Macedo, Gabriel S, Martelotto, Luciano G, de Bruijn, Ino, De Filippo, Maria R, Schultheis, Anne M, Ioris, Rafael A, Levine, Douglas A, Soslow, Robert A, Rubin, Brian P, Reis-Filho, Jorge S, Weigelt, Britta
Format Journal Article
LanguageEnglish
Published Chichester, UK John Wiley & Sons, Ltd 01.02.2016
Wiley Subscription Services, Inc
Subjects
Adenosarcoma - genetics
Adenosarcoma - pathology
Female
FISH
Gene Fusion - genetics
High-Throughput Nucleotide Sequencing
Humans
In Situ Hybridization
massively parallel sequencing
Mutation - genetics
Neoplasm Proteins - genetics
RNA sequencing
Sequence Analysis, RNA
uterine adenosarcoma
Uterine Neoplasms - genetics
Uterine Neoplasms - pathology
RNA sequencing
FISH
uterine adenosarcoma
massively parallel sequencing
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Summary: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. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Bibliography:Supplementary materials and methodsTERT and MDM2 amplifications in uterine adenosarcomas (UAs). (A) Copy number profiles of the UAs with TERT and MDM2 amplification; in the genome plots, smoothed log2 ratios (y axis) were plotted according to their genomic positions (x axis). (B) Copy number quantitative PCR results of the UAs with/without TERT and/or MDM2 amplificationValidation of selected mutations identified by targeted capture massively parallel sequencing in uterine adenosarcomas, using Sanger sequencing. Sanger sequencing traces of selected mutations identified in uterine adenosarcomas. Mutations are highlighted with a black arrowTERT and MDM2 amplifications in uterine adenosarcomas assessed by fluorescence in situ hybridization (FISH): representative FISH micrographs of (A) case BAS03 (TERT); (B) case BAS06 (TERT); (C) case BAS10 (TERT); (D) case BAS03 (MDM2); (E) case BAS10 (MDM2); (F) case BAS12 (MDM2); and (G) case BAS12 (MDM2). FISH analysis was performed using two-colour probes for MDM2 and hTERT full-length sequence (red) and internal control (green)Whole-exome and targeted capture massively parallel sequencing statisticsSomatic single nucleotide variants (SNVs) and insertion/deletions (indels) identified by whole-exome and targeted capture massively parallel sequencing in the uterine adenosarcomas studiedExpressed fusion transcripts identified in uterine adenosarcomas by RNA sequencingOverview of uterine adenosarcomas subjected to fluorescence in situ hybridization (FISH) of NCOA2, NCOA3, TERT and MDM2, to ESR1-NCOA2 and ESR1-NCOA3 RT-PCR, and to TERT and MDM2 copy number alteration quantitative real-time PCR (CNA qPCR) analysisComparisons of the mutational frequencies of the 341 genes included in our targeted capture panel between gynaecological carcinosarcomas reported by Jones et al and uterine adenosarcomas included in this studyList of primers used for the validation of mutations by Sanger sequencing, for the validation of selected fusion genes by RT-PCR and for the mitochondrial DNA D-loop region (GAMDDL) assay
National Institutes of Health/National Cancer Institute, USA - No. P30CA008748
ArticleID:PATH4675
istex:F6CB56C79B0B79D309B6148B85A14FEAE618C886
CAPES - No. BEX 5714/14-1
ark:/67375/WNG-XGH50M42-1
German Cancer Aid (Dr Mildred Scheel Stiftung)
Susan G Komen Postdoctoral Fellowship - No. PDF14298348
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-3417
1096-9896
DOI:10.1002/path.4675