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.

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., Edelweiss, M., Wen, H.-C., Piscuoglio, S., Schultheis, A. M., Martelotto, L. G., Pareja, F., Brandes, A., Lozada, J., Macedo, G. S., de Filippo, M. R., Jungbluth, A. A., Foschini, M. P., Wen, H. Y., Brogi, E., …Reis-Filho, J. S. (2018). Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas. Nature Communications, 9, Article 1816. 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: https://nottingham-repository.worktribe.com/output/931264
• Contract Date: Apr 10, 2018