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Open AccessArticle

Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease

1
Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
2
Medical Genomics Center, Nagoya University Hospital, Nagoya 466-8550, Japan
3
Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
4
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(4), 820; https://doi.org/10.3390/cancers12040820
Received: 15 March 2020 / Revised: 26 March 2020 / Accepted: 27 March 2020 / Published: 29 March 2020
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 FOXA1 mutations, a GAS6–FOXA1 fusion gene, and somatic hotspot mutations in the FOXA1 promoter region in 11 of the 48 EMPD patients (11/48, 23%). Additional mutations were identified in PIK3CA (six patients) and in HIST1H2BB, HIST1H2BC, and SMARCB1 (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. ABCC11, 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 FOXA1 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. View Full-Text
Keywords: extramammary Paget’s disease; forkhead box A1; fusion gene; mammary Paget’s disease; somatic mutations; whole-genome sequencing extramammary Paget’s disease; forkhead box A1; fusion gene; mammary Paget’s disease; somatic mutations; whole-genome sequencing
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Takeichi, T.; Okuno, Y.; Matsumoto, T.; Tsunoda, N.; Suzuki, K.; Tanahashi, K.; Kono, M.; Kikumori, T.; Muro, Y.; Akiyama, M. Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease. Cancers 2020, 12, 820.

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