Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas.
Felipe C GeyerAnqi LiAnastasios D PapanastasiouAlison SmithPier SelenicaKathleen A BurkeMarcia EdelweissHuei-Chi WenSalvatore PiscuoglioAnne M SchultheisLuciano G MartelottoFresia ParejaRahul KumarAlissa BrandesDan FanThais BasiliArnaud Da Cruz PaulaJohn R LozadaPedro BlecuaSimone MuenstAchim A JungbluthMaria P FoschiniHannah Y WenEdi BrogiJuan PalazzoBrian P RubinCharlotte C K NgLarry NortonZsuzsanna VargaIan O EllisEmad A RakhaSarat ChandarlapatyBritta WeigeltJorge S Reis-FilhoPublished in: Nature communications (2018)
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.