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.
Highlights
Adenomyoepithelioma of the breast is a rare tumor characterized by epithelial−myoepithelial differentiation, whose genetic underpinning is largely unknown
We report on a combination of whole-exome (WES) and targeted capture massively parallel sequencing analyses that revealed that adenomyoepitheliomas are genetically heterogeneous and that, akin to common-type breast cancers, their repertoire of somatic mutations vary according to their estrogen receptor (ER) status
Here we demonstrate that breast adenomyoepitheliomas constitute a heterogeneous group of tumors, characterized by recurrent pathogenic somatic mutations in HRAS and PI3K-AKT pathway genes
Summary
Adenomyoepithelioma of the breast is a rare tumor characterized by epithelial−myoepithelial differentiation, whose genetic underpinning is largely unknown. Large-scale massively parallel sequencing studies have revealed that breast cancers display a complex repertoire of somatic mutations, that TP53 (37%), PIK3CA (36%), and GATA3 (11%) are the only three genes recurrently mutated in >10% of unselected breast cancers, and that the repertoire of somatic mutations differs between ERpositive and ER-negative disease; no pathognomonic mutations underpinning ER-positive or ER-negative breast cancers have been identified[6,7] These analyses, primarily focused on the common forms of breast cancer[6,7,8], whereas the genetic characteristics of rare forms of breast tumors, including those with myoepithelial differentiation, remain largely unexplored[5]. In non-malignant triple-negative breast epithelial cells with or without a somatic knock-in of a PIK3CA H1047R mutation, forced expression of mutant HRAS promotes growth advantage, the acquisition of features consistent with myoepithelial differentiation, and activation of PI3K-AKT and MAPK signaling pathways, likely acting as a driver of ER-negative adenomyoepitheliomas
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