TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer

Abstract Metaplastic breast cancers (MBCs) are characterized by complex genomes, which seem to vary according to their histologic subtype. TERT promoter hotspot mutations and gene amplification are rare in common forms of breast cancer, but present in a subset of phyllodes tumors. Here, we sought to...

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Autores principales:	Edaise M. da Silva, Pier Selenica, Mahsa Vahdatinia, Fresia Pareja, Arnaud Da Cruz Paula, Lorenzo Ferrando, Andrea M. Gazzo, Higinio Dopeso, Dara S. Ross, Ariya Bakhteri, Nadeem Riaz, Sarat Chandarlapaty, Pedram Razavi, Larry Norton, Hannah Y. Wen, Edi Brogi, Britta Weigelt, Hong Zhang, Jorge S. Reis-Filho
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/f132c81e88b1476593e2db603427ca32
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spelling	oai:doaj.org-article:f132c81e88b1476593e2db603427ca322021-12-02T14:30:23ZTERT promoter hotspot mutations and gene amplification in metaplastic breast cancer10.1038/s41523-021-00250-82374-4677https://doaj.org/article/f132c81e88b1476593e2db603427ca322021-04-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00250-8https://doaj.org/toc/2374-4677Abstract Metaplastic breast cancers (MBCs) are characterized by complex genomes, which seem to vary according to their histologic subtype. TERT promoter hotspot mutations and gene amplification are rare in common forms of breast cancer, but present in a subset of phyllodes tumors. Here, we sought to determine the frequency of genetic alterations affecting TERT in a cohort of 60 MBCs with distinct predominant metaplastic components (squamous, 23%; spindle, 27%; osseous, 8%; chondroid, 42%), and to compare the repertoire of genetic alterations of MBCs according to the presence of TERT promoter hotspot mutations or gene amplification. Forty-four MBCs were subjected to: whole-exome sequencing (WES; n = 27) or targeted sequencing of 341-468 cancer-related genes (n = 17); 16 MBCs were subjected to Sanger sequencing of the TERT promoter, TP53 and selected exons of PIK3CA, HRAS, and BRAF. TERT promoter hotspot mutations (n = 9) and TERT gene amplification (n = 1) were found in 10 of the 60 MBCs analyzed, respectively. These TERT alterations were less frequently found in MBCs with predominant chondroid differentiation than in other MBC subtypes (p = 0.01, Fisher’s exact test) and were mutually exclusive with TP53 mutations (p < 0.001, CoMEt). In addition, a comparative analysis of the MBCs subjected to WES or targeted cancer gene sequencing (n = 44) revealed that MBCs harboring TERT promoter hotspot mutations or gene amplification (n = 6) more frequently harbored PIK3CA than TERT wild-type MBCs (n = 38; p = 0.001; Fisher’s exact test). In conclusion, TERT somatic genetic alterations are found in a subset of TP53 wild-type MBCs with squamous/spindle differentiation, highlighting the genetic diversity of these cancers.Edaise M. da SilvaPier SelenicaMahsa VahdatiniaFresia ParejaArnaud Da Cruz PaulaLorenzo FerrandoAndrea M. GazzoHiginio DopesoDara S. RossAriya BakhteriNadeem RiazSarat ChandarlapatyPedram RazaviLarry NortonHannah Y. WenEdi BrogiBritta WeigeltHong ZhangJorge S. Reis-FilhoNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Edaise M. da Silva Pier Selenica Mahsa Vahdatinia Fresia Pareja Arnaud Da Cruz Paula Lorenzo Ferrando Andrea M. Gazzo Higinio Dopeso Dara S. Ross Ariya Bakhteri Nadeem Riaz Sarat Chandarlapaty Pedram Razavi Larry Norton Hannah Y. Wen Edi Brogi Britta Weigelt Hong Zhang Jorge S. Reis-Filho TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer
description	Abstract Metaplastic breast cancers (MBCs) are characterized by complex genomes, which seem to vary according to their histologic subtype. TERT promoter hotspot mutations and gene amplification are rare in common forms of breast cancer, but present in a subset of phyllodes tumors. Here, we sought to determine the frequency of genetic alterations affecting TERT in a cohort of 60 MBCs with distinct predominant metaplastic components (squamous, 23%; spindle, 27%; osseous, 8%; chondroid, 42%), and to compare the repertoire of genetic alterations of MBCs according to the presence of TERT promoter hotspot mutations or gene amplification. Forty-four MBCs were subjected to: whole-exome sequencing (WES; n = 27) or targeted sequencing of 341-468 cancer-related genes (n = 17); 16 MBCs were subjected to Sanger sequencing of the TERT promoter, TP53 and selected exons of PIK3CA, HRAS, and BRAF. TERT promoter hotspot mutations (n = 9) and TERT gene amplification (n = 1) were found in 10 of the 60 MBCs analyzed, respectively. These TERT alterations were less frequently found in MBCs with predominant chondroid differentiation than in other MBC subtypes (p = 0.01, Fisher’s exact test) and were mutually exclusive with TP53 mutations (p < 0.001, CoMEt). In addition, a comparative analysis of the MBCs subjected to WES or targeted cancer gene sequencing (n = 44) revealed that MBCs harboring TERT promoter hotspot mutations or gene amplification (n = 6) more frequently harbored PIK3CA than TERT wild-type MBCs (n = 38; p = 0.001; Fisher’s exact test). In conclusion, TERT somatic genetic alterations are found in a subset of TP53 wild-type MBCs with squamous/spindle differentiation, highlighting the genetic diversity of these cancers.
format	article
author	Edaise M. da Silva Pier Selenica Mahsa Vahdatinia Fresia Pareja Arnaud Da Cruz Paula Lorenzo Ferrando Andrea M. Gazzo Higinio Dopeso Dara S. Ross Ariya Bakhteri Nadeem Riaz Sarat Chandarlapaty Pedram Razavi Larry Norton Hannah Y. Wen Edi Brogi Britta Weigelt Hong Zhang Jorge S. Reis-Filho
author_facet	Edaise M. da Silva Pier Selenica Mahsa Vahdatinia Fresia Pareja Arnaud Da Cruz Paula Lorenzo Ferrando Andrea M. Gazzo Higinio Dopeso Dara S. Ross Ariya Bakhteri Nadeem Riaz Sarat Chandarlapaty Pedram Razavi Larry Norton Hannah Y. Wen Edi Brogi Britta Weigelt Hong Zhang Jorge S. Reis-Filho
author_sort	Edaise M. da Silva
title	TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer
title_short	TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer
title_full	TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer
title_fullStr	TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer
title_full_unstemmed	TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer
title_sort	tert promoter hotspot mutations and gene amplification in metaplastic breast cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f132c81e88b1476593e2db603427ca32
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TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer

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