Skip to main content

Research Repository

Advanced Search

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

Geyer, Felipe C.; Li, Anqi; Papanastasiou, Anastasios D.; Smith, Alison; Selenica, Pier; Burke, Kathleen A.; Edelweiss, Marcia; Wen, Huei-Chi; Piscuoglio, Salvatore; Schultheis, Anne M.; Martelotto, Luciano G.; Pareja, Fresia; Brandes, Alissa; Lozada, John; Macedo, Gabriel S.; de Filippo, Maria R.; Jungbluth, Achim A.; Foschini, Maria Pia; Wen, Hannah Y.; Brogi, Edi; Palazzo, Juan; Rubin, Brian P.; Ng, Charlotte K.Y.; Norton, Larry; Rakha, Emad A.; Varga, Zsuzsanna; Ellis, Ian O.; Chandarlapaty, Sarat; Weigelt, Britta; Reis-Filho, Jorge S.

Authors

Felipe C. Geyer

Anqi Li

Anastasios D. Papanastasiou

Alison Smith

Pier Selenica

Kathleen A. Burke

Marcia Edelweiss

Huei-Chi Wen

Salvatore Piscuoglio

Anne M. Schultheis

Luciano G. Martelotto

Fresia Pareja

Alissa Brandes

John Lozada

Gabriel S. Macedo

Maria R. de Filippo

Achim A. Jungbluth

Maria Pia Foschini

Hannah Y. Wen

Edi Brogi

Juan Palazzo

Brian P. Rubin

Charlotte K.Y. Ng

Larry Norton

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Zsuzsanna Varga

Sarat Chandarlapaty

Britta Weigelt

Jorge S. Reis-Filho



Abstract

Adenomyoepithelioma of the breast is a rare tumor characterized by epithelial-myoepithelial differentiation, of which a subset will progress to invasive or metastatic cancer. We sought to define the genomic landscape of adenomyoepitheliomas. Massively parallel sequencing revealed highly recurrent somatic mutations in HRAS and PI3K-AKT pathway-related genes. Strikingly, HRAS mutations were restricted to estrogen receptor (ER)-negative tumors, all affected codon 61, and all but one co-occurred with PIK3CA or PIK3R1 mutations. To interrogate the functional significance of HRAS Q61 mutations in adenomyoepithelial differentiation, we expressed HRASQ61R alone or in combination with PIK3CAH1047R in non-transformed ER-negative breast epithelial cells. HRASQ61R induced characteristic phenotypes of adenomyoepitheliomas such as the expression of myoepithelial markers and loss of e-cadherin, hyperactivation of AKT signaling, and transformative properties that were arrested by combination therapy with AKT and MEK inhibitors. Our results indicate that breast adenomyoepitheliomas often manifest a unique transformation program featuring HRAS activation.

Citation

Geyer, F. C., Li, A., Papanastasiou, A. D., Smith, A., Selenica, P., Burke, K. A., …Reis-Filho, J. S. (2018). Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas. Nature Communications, 9, https://doi.org/10.1038/s41467-018-04128-5

Journal Article Type Article
Acceptance Date Apr 6, 2018
Publication Date May 8, 2018
Deposit Date Apr 10, 2018
Publicly Available Date May 8, 2018
Journal Nature Communications
Electronic ISSN 2041-1723
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 9
Article Number 1816
DOI https://doi.org/10.1038/s41467-018-04128-5
Keywords epithelial-myoepithelial carcinoma, breast cancer, copy number variation, single nucleotide variant, RNA-sequencing, whole-exome sequencing
Public URL http://eprints.nottingham.ac.uk/id/eprint/51065
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

Files

s41467-018-04128-5.pdf (7.8 Mb)
PDF

Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





You might also like



Downloadable Citations