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Breast adenomyoepitheliomas (AMEs) are rare epithelial-myoepithelial neoplasms that may occasionally produce myxochondroid matrix, akin to pleomorphic adenomas (PAs). Regardless of their anatomic location, PAs often harbor rearrangements involving  HMGA2  or  PLAG1 . We have recently shown that the repertoire of somatic genetic alterations of AMEs varies according to their estrogen receptor (ER) status; whilst the majority of ER-positive AMEs display mutually exclusive  PIK3CA  or  AKT1  hotspot mutations, up to 60% of ER-negative AMEs harbor concurrent  HRAS  Q61 hotspot mutations and mutations affecting either  PIK3CA  or  PIK3R1 . Here, we hypothesized that a subset of AMEs lacking these somatic genetic alterations could be underpinned by oncogenic fusion genes, in particular those involving  HMGA2  or  PLAG1 . Therefore, we subjected 13 AMEs to RNA-sequencing for fusion discovery ( n  = 5) and/or fluorescence in situ hybridization (FISH) analysis for  HMGA2  and  PLAG1  rearrangements ( n  = 13). RNA-sequencing revealed an  HMGA2 - WIF1  fusion gene in an ER-positive AME lacking  HRAS, PIK3CA  and  AKT1  somatic mutations. This fusion gene, which has been previously described in salivary gland PAs, results in a chimeric transcript composed of exons 1–5 of  HMGA2  and exons 3–10 of  WIF1 . No additional in-frame fusion genes or  HMGA2  or  PLAG1  rearrangements were identified in the remaining AMEs analyzed. Our results demonstrate that a subset of AMEs lacking mutations affecting  HRAS  and PI3K pathway-related genes may harbor  HMGA2 - WIF1  fusion genes, suggesting that a subset of breast AMEs may be genetically related to PAs or that a subset of AMEs may originate in the context of a PA.

Assessment of HMGA2 and PLAG1 rearrangements in breast adenomyoepitheliomas