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
  • 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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