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Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas

Geyer, Felipe C. and Li, Anqi and Papanastasiou, Anastasios D. and Smith, Alison and Selenica, Pier and Burke, Kathleen A. and Edelweiss, Marcia and Wen, Huei-Chi and Piscuoglio, Salvatore and Schultheis, Anne M. and Martelotto, Luciano G. and Pareja, Fresia and Kumar, Rahul and Brandes, Alissa and Fan, Dan and Basili, Thais and Da Cruz Paula, Arnaud and Lozada, John R. and Blecua, Pedro and Muenst, Simone and Jungbluth, Achim A. and Foschini, Maria P. and Wen, Hannah Y. and Brogi, Edi and Palazzo, Juan and Rubin, Brian P. and Ng, Charlotte K. Y. and Norton, Larry and Varga, Zsuzsanna and Ellis, Ian O. and Rakha, Emad A. and Chandarlapaty, Sarat and Weigelt, Britta and Reis-Filho, Jorge S.. (2018) Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas. Nature communications, 9 (1). p. 1816.

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Abstract

Adenomyoepithelioma of the breast is a rare tumor characterized by epithelial-myoepithelial differentiation, whose genetic underpinning is largely unknown. Here we show through whole-exome and targeted massively parallel sequencing analysis that whilst estrogen receptor (ER)-positive adenomyoepitheliomas display PIK3CA or AKT1 activating mutations, ER-negative adenomyoepitheliomas harbor highly recurrent codon Q61 HRAS hotspot mutations, which co-occur with PIK3CA or PIK3R1 mutations. In two- and three-dimensional cell culture models, forced expression of HRAS; Q61R; in non-malignant ER-negative breast epithelial cells with or without a PIK3CA; H1047R; somatic knock-in results in transformation and the acquisition of the cardinal features of adenomyoepitheliomas, including the expression of myoepithelial markers, a reduction in E-cadherin expression, and an increase in AKT signaling. Our results demonstrate that adenomyoepitheliomas are genetically heterogeneous, and qualify mutations in HRAS, a gene whose mutations are vanishingly rare in common-type breast cancers, as likely drivers of ER-negative adenomyoepitheliomas.
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:Nature Research
ISSN:2041-1723
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:29 Jan 2019 09:05
Deposited On:29 Jan 2019 09:05

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