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Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor

Phyllodes tumors (PTs) and fibroadenomas (FAs) are fibroepithelial lesions (FELs) of the breast. Although mutations affecting exon 2 of MED12 are highly recurrent in FAs and PTs, TERT promoter hotspot mutations are frequently found in PTs but are vanishingly rare in FAs. Malignant transformation of...

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Autores principales: Piscuoglio, Salvatore, Geyer, Felipe C, Burke, Kathleen A, Murray, Melissa P, Ng, Charlotte KY, Mota, Alba, Marchio, Caterina, Berman, Samuel H, Norton, Larry, Brogi, Edi, Weigelt, Britta, Reis-Filho, Jorge S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515337/
https://www.ncbi.nlm.nih.gov/pubmed/28721388
http://dx.doi.org/10.1038/npjbcancer.2016.35
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author Piscuoglio, Salvatore
Geyer, Felipe C
Burke, Kathleen A
Murray, Melissa P
Ng, Charlotte KY
Mota, Alba
Marchio, Caterina
Berman, Samuel H
Norton, Larry
Brogi, Edi
Weigelt, Britta
Reis-Filho, Jorge S
author_facet Piscuoglio, Salvatore
Geyer, Felipe C
Burke, Kathleen A
Murray, Melissa P
Ng, Charlotte KY
Mota, Alba
Marchio, Caterina
Berman, Samuel H
Norton, Larry
Brogi, Edi
Weigelt, Britta
Reis-Filho, Jorge S
author_sort Piscuoglio, Salvatore
collection PubMed
description Phyllodes tumors (PTs) and fibroadenomas (FAs) are fibroepithelial lesions (FELs) of the breast. Although mutations affecting exon 2 of MED12 are highly recurrent in FAs and PTs, TERT promoter hotspot mutations are frequently found in PTs but are vanishingly rare in FAs. Malignant transformation of benign PTs is well-documented, but the progression from FA to PT remains a matter of contention. Here we report on the somatic genetic alterations in multiple ipsilateral synchronous FELs (three FAs, one benign PT, and one malignant PT) occurring in the same patient. DNA samples extracted from each tumor and matched normal tissue were subjected to targeted massively parallel sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. This analysis revealed MED12 mutations in all lesions. One FA and the benign PT harbored a MED12(Gly44Val) mutation, whereas another FA and the malignant PT displayed a MED12(Gly44Asp) mutation. The remaining FA had an independent distinct MED12(Gly44Cys) mutation. A formal clonality analysis suggested a clonal relationship between the FELs with identical MED12 mutations (P<0.05). A clonal TERT promoter hotspot mutation was identified exclusively in the malignant PT. The identification of distinct MED12 mutations in multifocal ipsilateral and synchronous FELs supports the notion that co-existing mammary fibroepithelial tumors can arise independently. Conversely, the co-existence of identical MED12 mutations indicates clonal relatedness among FAs and PTs, corroborating the hypothesis that FAs may constitute the substrate from which PTs develop. Our findings also support the notion that acquisition of TERT promoter mutations may drive the progression of FELs.
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spelling pubmed-55153372017-07-18 Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor Piscuoglio, Salvatore Geyer, Felipe C Burke, Kathleen A Murray, Melissa P Ng, Charlotte KY Mota, Alba Marchio, Caterina Berman, Samuel H Norton, Larry Brogi, Edi Weigelt, Britta Reis-Filho, Jorge S NPJ Breast Cancer Article Phyllodes tumors (PTs) and fibroadenomas (FAs) are fibroepithelial lesions (FELs) of the breast. Although mutations affecting exon 2 of MED12 are highly recurrent in FAs and PTs, TERT promoter hotspot mutations are frequently found in PTs but are vanishingly rare in FAs. Malignant transformation of benign PTs is well-documented, but the progression from FA to PT remains a matter of contention. Here we report on the somatic genetic alterations in multiple ipsilateral synchronous FELs (three FAs, one benign PT, and one malignant PT) occurring in the same patient. DNA samples extracted from each tumor and matched normal tissue were subjected to targeted massively parallel sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. This analysis revealed MED12 mutations in all lesions. One FA and the benign PT harbored a MED12(Gly44Val) mutation, whereas another FA and the malignant PT displayed a MED12(Gly44Asp) mutation. The remaining FA had an independent distinct MED12(Gly44Cys) mutation. A formal clonality analysis suggested a clonal relationship between the FELs with identical MED12 mutations (P<0.05). A clonal TERT promoter hotspot mutation was identified exclusively in the malignant PT. The identification of distinct MED12 mutations in multifocal ipsilateral and synchronous FELs supports the notion that co-existing mammary fibroepithelial tumors can arise independently. Conversely, the co-existence of identical MED12 mutations indicates clonal relatedness among FAs and PTs, corroborating the hypothesis that FAs may constitute the substrate from which PTs develop. Our findings also support the notion that acquisition of TERT promoter mutations may drive the progression of FELs. Nature Publishing Group 2016-11-16 /pmc/articles/PMC5515337/ /pubmed/28721388 http://dx.doi.org/10.1038/npjbcancer.2016.35 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Piscuoglio, Salvatore
Geyer, Felipe C
Burke, Kathleen A
Murray, Melissa P
Ng, Charlotte KY
Mota, Alba
Marchio, Caterina
Berman, Samuel H
Norton, Larry
Brogi, Edi
Weigelt, Britta
Reis-Filho, Jorge S
Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor
title Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor
title_full Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor
title_fullStr Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor
title_full_unstemmed Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor
title_short Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor
title_sort massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515337/
https://www.ncbi.nlm.nih.gov/pubmed/28721388
http://dx.doi.org/10.1038/npjbcancer.2016.35
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