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

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, Rahul Kumar, Alissa Brandes, Dan Fan, Thais Basili, Arnaud Paula, John R. Lozada, Pedro Blecua, Simone Muenst, Achim A. Jungbluth, Maria P. Foschini, Hannah Y. Wen, Edi Brogi, Juan Palazzo, Brian P. Rubin, Charlotte K. Y. Ng, Larry Norton, Zsuzsanna Varga, Ian O. Ellis, Emad A. Rakha, Sarat Chandarlapaty, Britta Weigelt () and Jorge S. Reis-Filho ()
Additional contact information
Felipe C. Geyer: Memorial Sloan Kettering Cancer Center
Anqi Li: Memorial Sloan Kettering Cancer Center
Anastasios D. Papanastasiou: Memorial Sloan Kettering Cancer Center
Alison Smith: Memorial Sloan Kettering Cancer Center
Pier Selenica: Memorial Sloan Kettering Cancer Center
Kathleen A. Burke: Memorial Sloan Kettering Cancer Center
Marcia Edelweiss: Memorial Sloan Kettering Cancer Center
Huei-Chi Wen: Memorial Sloan Kettering Cancer Center
Salvatore Piscuoglio: Memorial Sloan Kettering Cancer Center
Anne M. Schultheis: Memorial Sloan Kettering Cancer Center
Luciano G. Martelotto: Memorial Sloan Kettering Cancer Center
Fresia Pareja: Memorial Sloan Kettering Cancer Center
Rahul Kumar: Memorial Sloan Kettering Cancer Center
Alissa Brandes: Memorial Sloan Kettering Cancer Center
Dan Fan: Memorial Sloan Kettering Cancer Center
Thais Basili: Memorial Sloan Kettering Cancer Center
Arnaud Paula: Memorial Sloan Kettering Cancer Center
John R. Lozada: Memorial Sloan Kettering Cancer Center
Pedro Blecua: Memorial Sloan Kettering Cancer Center
Simone Muenst: University Hospital Basel
Achim A. Jungbluth: Memorial Sloan Kettering Cancer Center
Maria P. Foschini: Section of Bellaria Hospital
Hannah Y. Wen: Memorial Sloan Kettering Cancer Center
Edi Brogi: Memorial Sloan Kettering Cancer Center
Juan Palazzo: Thomas Jefferson University Hospital
Brian P. Rubin: Cleveland Clinic
Charlotte K. Y. Ng: Memorial Sloan Kettering Cancer Center
Larry Norton: Memorial Sloan Kettering Cancer Center
Zsuzsanna Varga: University Hospital Zurich
Ian O. Ellis: University of Nottingham
Emad A. Rakha: University of Nottingham
Sarat Chandarlapaty: Memorial Sloan Kettering Cancer Center
Britta Weigelt: Memorial Sloan Kettering Cancer Center
Jorge S. Reis-Filho: Memorial Sloan Kettering Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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 HRASQ61R in non-malignant ER-negative breast epithelial cells with or without a PIK3CAH1047R 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.

Date: 2018
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DOI: 10.1038/s41467-018-04128-5

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