Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas
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 so...
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Nature Publishing Group
2018
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| author | 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. |
| author_facet | 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. |
| author_sort | Geyer, Felipe C. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:19:15Z |
| format | Article |
| id | nottingham-51065 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:19:15Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-510652020-05-04T19:35:41Z https://eprints.nottingham.ac.uk/51065/ 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. 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. Nature Publishing Group 2018-05-08 Article PeerReviewed 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 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 epithelial-myoepithelial carcinoma breast cancer copy number variation single nucleotide variant RNA-sequencing whole-exome sequencing doi:10.1038/s41467-018-04128-5 doi:10.1038/s41467-018-04128-5 |
| spellingShingle | epithelial-myoepithelial carcinoma breast cancer copy number variation single nucleotide variant RNA-sequencing whole-exome sequencing 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. Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas |
| title | Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas |
| title_full | Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas |
| title_fullStr | Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas |
| title_full_unstemmed | Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas |
| title_short | Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas |
| title_sort | recurrent hotspot mutations in hras q61 and pi3k-akt pathway genes as drivers of breast adenomyoepitheliomas |
| topic | epithelial-myoepithelial carcinoma breast cancer copy number variation single nucleotide variant RNA-sequencing whole-exome sequencing |
| url | https://eprints.nottingham.ac.uk/51065/ https://eprints.nottingham.ac.uk/51065/ |