Frequent FOXA1 -Activating Mutations in Extramammary Paget's Disease

Extramammary Paget's disease (EMPD) is a neoplastic skin disease of indeterminate origin with an unknown genetic cause. We performed a comprehensive genetic analysis or targeted gene sequencing in 48 patients with EMPD. We identified mutations, a fusion gene, and somatic hotspot mutations in the promoter region in 11 of the 48 EMPD patients (11/48, 23%). Additional mutations were identified in (six patients) and in , , and (one patient each), but none were found in other frequently mutated genes in cancer. A global gene expression analysis using EMPD clinical samples found the upregulation of PI3 kinase-AKT-mTOR signaling. , which is specifically expressed in the apocrine secretory cells and is necessary for their sweat secretion, was upregulated in the EMPD samples. This upregulation suggests that Paget cells originate from apocrine secretory cells. Immunohistochemical staining revealed that FOXA1 expression was prevalent in all of the EMPD samples analyzed and was associated with estrogen receptor expression. Our genetic analysis indicates that EMPD frequently involves mutations. FOXA1 is a transcriptional pioneer factor for the estrogen receptor, and the present results suggest that certain treatments for hormone-dependent cancers could be effective for EMPD.