1. Academic Validation
  2. Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas

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

  • Nat Commun. 2018 May 8;9(1):1816. doi: 10.1038/s41467-018-04128-5.
Felipe C Geyer 1 2 3 Anqi Li 1 4 Anastasios D Papanastasiou 1 5 Alison Smith 6 Pier Selenica 1 Kathleen A Burke 1 Marcia Edelweiss 1 Huei-Chi Wen 1 Salvatore Piscuoglio 1 7 Anne M Schultheis 1 Luciano G Martelotto 1 Fresia Pareja 1 Rahul Kumar 1 Alissa Brandes 1 Dan Fan 1 8 Thais Basili 1 Arnaud Da Cruz Paula 1 John R Lozada 1 Pedro Blecua 9 Simone Muenst 7 Achim A Jungbluth 1 Maria P Foschini 10 Hannah Y Wen 1 Edi Brogi 1 Juan Palazzo 11 Brian P Rubin 12 Charlotte K Y Ng 1 7 13 Larry Norton 14 Zsuzsanna Varga 15 Ian O Ellis 16 Emad A Rakha 16 Sarat Chandarlapaty 6 Britta Weigelt 17 Jorge S Reis-Filho 18 19
Affiliations

Affiliations

  • 1 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 2 Hospital Israelita Albert Einstein, Instituto Israelita de Ensino e Pesquisa, São Paulo, 05652-900, Brazil.
  • 3 Instituto do Cancer do Estado de São Paulo, São Paulo, 01246-000, Brazil.
  • 4 Department of Pathology, Fudan University Shanghai Cancer Center, 200032, Shanghai, PR China.
  • 5 Department of Pathology, Patras General Hospital, 263 32, Patras, Greece.
  • 6 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 7 Institute of Pathology and Medical Genetics, University Hospital Basel, 4031, Basel, Switzerland.
  • 8 Department of Oncology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan Province, PR China.
  • 9 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 10 Department of Biomedical and Neuromotor Sciences, University of Bologna, Section of Bellaria Hospital, 40139, Bologna, Italy.
  • 11 Department of Pathology, Thomas Jefferson University Hospital, Philadelphia, PA, 19107, USA.
  • 12 Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
  • 13 Department of Biomedicine, University of Basel, 4001, Basel, Switzerland.
  • 14 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 15 Institute of Surgical Pathology, University Hospital Zurich, 8091, Zurich, Switzerland.
  • 16 Department of Pathology, University of Nottingham, Nottingham, NG7 2RD, UK.
  • 17 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. weigeltb@mskcc.org.
  • 18 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. reisfilj@mskcc.org.
  • 19 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. reisfilj@mskcc.org.
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.

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