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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 FOXA1 mutations, a GAS6–FOXA1 fusion gene, and somatic hotspot mut...

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Autores principales: Takeichi, Takuya, Okuno, Yusuke, Matsumoto, Takaaki, Tsunoda, Nobuyuki, Suzuki, Kyogo, Tanahashi, Kana, Kono, Michihiro, Kikumori, Toyone, Muro, Yoshinao, Akiyama, Masashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226542/
https://www.ncbi.nlm.nih.gov/pubmed/32235312
http://dx.doi.org/10.3390/cancers12040820
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author Takeichi, Takuya
Okuno, Yusuke
Matsumoto, Takaaki
Tsunoda, Nobuyuki
Suzuki, Kyogo
Tanahashi, Kana
Kono, Michihiro
Kikumori, Toyone
Muro, Yoshinao
Akiyama, Masashi
author_facet Takeichi, Takuya
Okuno, Yusuke
Matsumoto, Takaaki
Tsunoda, Nobuyuki
Suzuki, Kyogo
Tanahashi, Kana
Kono, Michihiro
Kikumori, Toyone
Muro, Yoshinao
Akiyama, Masashi
author_sort Takeichi, Takuya
collection PubMed
description 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.
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spelling pubmed-72265422020-05-18 Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease Takeichi, Takuya Okuno, Yusuke Matsumoto, Takaaki Tsunoda, Nobuyuki Suzuki, Kyogo Tanahashi, Kana Kono, Michihiro Kikumori, Toyone Muro, Yoshinao Akiyama, Masashi Cancers (Basel) Article 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. MDPI 2020-03-29 /pmc/articles/PMC7226542/ /pubmed/32235312 http://dx.doi.org/10.3390/cancers12040820 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Takeichi, Takuya
Okuno, Yusuke
Matsumoto, Takaaki
Tsunoda, Nobuyuki
Suzuki, Kyogo
Tanahashi, Kana
Kono, Michihiro
Kikumori, Toyone
Muro, Yoshinao
Akiyama, Masashi
Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease
title Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease
title_full Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease
title_fullStr Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease
title_full_unstemmed Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease
title_short Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease
title_sort frequent foxa1-activating mutations in extramammary paget’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226542/
https://www.ncbi.nlm.nih.gov/pubmed/32235312
http://dx.doi.org/10.3390/cancers12040820
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