Frequent FOXA1-Activating Mutations in Extramammary Paget's Disease.

Takuya Takeichi,Toyone Kikumori,Michihiro Kono,Kana Tanahashi,Masashi Akiyama,Yoshinao Muro,Yusuke Okuno,Nobuyuki Tsunoda,Takaaki Matsumoto,Kyogo Suzuki

doi:10.3390/cancers12040820

Takuya Takeichi, Toyone Kikumori + Show 8 more

Open Access

https://doi.org/10.3390/cancers12040820

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Journal: Cancers	Publication Date: Mar 29, 2020
Citations: 16	License type: CC BY 4.0

Affiliation: Nagoya University, Nagoya University Hospital

Abstract

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.

Highlights

Paget’s disease (PD) is a neoplasm seen on the nipple/areola or in extramammary body zones, such as in anogenital and perineal skin and the axilla [1]
GAS6–FOXA1, we considered that the function of this gene fusion is to upregulate the transcriptional activity of FOXA1 using GAS6 promoter activity
We identified the GAS6–FOXA1 fusion in an Extramammary Paget’s disease (EMPD) case and recurrent hotspot mutations in the FOXA1 promoter in 10 EMPD patients

Summary

Introduction

Paget’s disease (PD) is a neoplasm seen on the nipple/areola (mammary PD; MPD) or in extramammary body zones, such as in anogenital and perineal skin and the axilla MPD is relatively rare, observed in 0.7–4.3% of all breast cancers. It is much more frequent in women, possibly because of the clear predominance of breast cancer in females MPD develops more often in people in their fifties (mean age: 57 years), i.e., in 70% of MPD cases in postmenopausal women, but it has been observed in adolescents and in elderly patients [1]. EMPD was first described by Crocker in 1889 [2].

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