edoc

The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas

Ng, Charlotte K. Y. and Piscuoglio, Salvatore and Geyer, Felipe C. and Burke, Kathleen A. and Pareja, Fresia and Eberle, Carey A. and Lim, Raymond S. and Natrajan, Rachael and Riaz, Nadeem and Mariani, Odette and Norton, Larry and Vincent-Salomon, Anne and Wen, Y. Hannah and Weigelt, Britta and Reis-Filho, Jorge S.. (2017) The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas. Clinical cancer research, 23 (14). pp. 3859-3870.

[img] PDF - Accepted Version
1088Kb

Official URL: https://edoc.unibas.ch/68143/

Downloads: Statistics Overview

Abstract

Purpose:; Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic type of breast cancer, predominantly of triple-negative phenotype, and characterized by the presence of malignant cells showing squamous and/or mesenchymal differentiation. We sought to define the repertoire of somatic genetic alterations and the mutational signatures of MBCs.; Experimental Design:; Whole-exome sequencing was performed in 35 MBCs, with 16, 10, and 9 classified as harboring chondroid, spindle, and squamous metaplasia as the predominant metaplastic component. The genomic landscape of MBCs was compared with that of triple-negative invasive ductal carcinomas of no special type (IDC-NST) from The Cancer Genome Atlas. Wnt and PI3K/AKT/mTOR pathway activity was assessed using a qPCR assay.; Results:; MBCs harbored complex genomes with frequent; TP53; (69%) mutations. In contrast to triple-negative IDC-NSTs, MBCs more frequently harbored mutations in; PIK3CA; (29%),; PIK3R1; (11%),; ARID1A; (11%),; FAT1; (11%), and; PTEN; (11%).; PIK3CA; mutations were not found in MBCs with chondroid metaplasia. Compared with triple-negative IDC-NSTs, MBCs significantly more frequently harbored mutations in PI3K/AKT/mTOR pathway-related (57% vs. 22%) and canonical Wnt pathway-related (51% vs. 28%) genes. MBCs with somatic mutations in PI3K/AKT/mTOR or Wnt pathway-related genes displayed increased activity of the respective pathway.; Conclusions:; MBCs are genetically complex and heterogeneous, and are driven by a repertoire of somatic mutations distinct from that of triple-negative IDC-NSTs. Our study highlights the genetic basis and the importance of PI3K/AKT/mTOR and Wnt pathway dysregulation in MBCs and provides a rationale for the metaplastic phenotype and the reported responses to PI3K/AKT/mTOR inhibitors in these tumors.
Faculties and Departments:03 Faculty of Medicine
03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB
UniBasel Contributors:Piscuoglio, Salvatore
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for Cancer Research
ISSN:1078-0432
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:25 Jan 2019 14:58
Deposited On:25 Jan 2019 14:55

Repository Staff Only: item control page