2. Academic Validation
  3. 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. [email protected].
  • 18 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
  • 19 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
PMID: 29739933 DOI: 10.1038/s41467-018-04128-5
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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