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 Brandes, Alissa and Lozada, John and Macedo, Gabriel S. and de Filippo, Maria R. and Jungbluth, Achim A. and Foschini, Maria Pia and Wen, Hannah Y. and Brogi, Edi and Palazzo, Juan and Rubin, Brian P. and Ng, Charlotte K.Y. and Norton, Larry and Rakha, Emad A. and Varga, Zsuzsanna and Ellis, Ian O. 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 . 1816/1-1816/16. ISSN 2041-1723

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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.

Item Type: Article
Keywords: epithelial-myoepithelial carcinoma, breast cancer, copy number variation, single nucleotide variant, RNA-sequencing, whole-exome sequencing
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences
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Depositing User: Eprints, Support
Date Deposited: 10 Apr 2018 13:18
Last Modified: 04 May 2020 19:35

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