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

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.

• Authors: 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 Da Cruz 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, Jorge S Reis-Filho
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 1816 (05 08 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29739933 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Cadherins
• Receptors, Estrogen
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Adenomyoepithelioma (enzymology, genetics, pathology)
• Biomarkers, Tumor (genetics)
• Breast (cytology, metabolism)
• Breast Neoplasms (enzymology, genetics, pathology)
• Cadherins (metabolism)
• Cell Differentiation
• Cell Line, Tumor
• Class I Phosphatidylinositol 3-Kinases (metabolism)
• Disease Progression
• Enzyme Activation
• Epithelial Cells (cytology, metabolism)
• Female
• Genes, ras
• Humans
• Mutation
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Estrogen (metabolism)
• Reproducibility of Results
• Signal Transduction
• Exome Sequencing