Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease

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

doi:10.3390/cancers12040820

Cited by 17 publications

(20 citation statements)

References 29 publications

(41 reference statements)

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“…Frequent gene alternations in ERBB2, RAS, RAF, AKT1, and PIK3C in EMPD lesions detected in previous studies suggested that HER2, which is encoded by ERBB2, and its downstream signaling, including RAS/RAF-MEK-ERK pathway and PI3K-AKT-mTOR pathway, may play important roles in the pathogenesis of EMPD in many cases. Takeichi et al also analyzed genomic alteration in 48 patients with EMPD and identified FOXA1 mutations, a GAS6-FOXA1 fusion gene, and somatic hotspot mutations in the FOXA1 promoter region in 11 of the 48 patients [53]. They also revealed that FOXA1 expression was strongly expressed in Paget cells in all of the EMPD samples and was associated with estrogen receptor (ER) expression [53].…”

Section: Pathogenesismentioning

confidence: 99%

“…Takeichi et al also analyzed genomic alteration in 48 patients with EMPD and identified FOXA1 mutations, a GAS6-FOXA1 fusion gene, and somatic hotspot mutations in the FOXA1 promoter region in 11 of the 48 patients [53]. They also revealed that FOXA1 expression was strongly expressed in Paget cells in all of the EMPD samples and was associated with estrogen receptor (ER) expression [53]. Given that FOXA1 assists the transcriptional activity of the ER and may be involved cooperatively in the tumorigenesis of breast cancer, the FOXA1-ER axis may also play crucial roles in EMPD development and progression in some cases [54].…”

Section: Pathogenesismentioning

confidence: 99%

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Extramammary Paget’s Disease: Diagnosis, Pathogenesis, and Treatment with Focus on Recent Developments

Ishizuki

Nakamura

2021

Current Oncology

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Extramammary Paget’s disease (EMPD) is a rare neoplasm that usually develops in apocrine gland-bearing areas, such as the vulva, scrotum, and penis. EMPD may present with a focal, multifocal, or an ectopic lesion. Clinically, EMPD lesions often exhibit infiltrative erythema, which is sometimes similar to other skin disorders such as eczema. While primary EMPD arises as intraepithelial neoplasm of the epidermis, EMPD-like lesions may occur from epidermotropic spread of malignant cells or direct extension from an underlying internal neoplasm, known as secondary EMPD. Because treatment strategies differ for primary EMPD and secondary EMPD, accurate diagnosis based on detailed histopathological evaluation is required. In the early stages, EMPD usually shows indolent growth, and most cases are diagnosed as carcinoma in situ. However, invasive lesions may result in metastases, and deep invasion is associated with high incidence of metastases. Conventional chemotherapies have been used for EMPD treatment in patients with distant metastases, but the efficacy is not satisfactory, and the prognosis for such patients remains poor. Recent studies have provided various insights into the molecular pathogenesis of the development and advancement of EMPD, which may lead to novel treatment approaches for metastatic EMPD. This review addresses the diagnosis, pathogenesis, and treatment of EMPD with focus on recent progress in understanding this disease.

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Section: Pathogenesismentioning

confidence: 99%

Section: Pathogenesismentioning

confidence: 99%

Extramammary Paget’s Disease: Diagnosis, Pathogenesis, and Treatment with Focus on Recent Developments

Ishizuki

Nakamura

2021

Current Oncology

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“…However, their efficacy in treating unresectable EMPD is unsatisfactory. Recently, several genomic profiling analyses using genomic sequencing were conducted in order to determine driver mutations in EMPD (21)(22)(23). Despite the progress made, new treatment modalities are required (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

CDK4: A Novel Therapeutic Target for Extramammary Paget’s Disease

et al. 2021

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BackgroundThe outcome of extramammary Paget’s disease (EMPD) is poor when it progresses to metastasis because of the lack of effective systemic therapies. Recently, CDK4-targeted therapy has attracted attention as a potential therapeutic target for some cancers. The aim of this study was to analyze the impact of CDK4 expression on the survival of patients with EMPD.MethodsWe retrospectively reviewed 110 patients with EMPD. We conducted immunohistochemical analysis of CDK4 and cyclin D1 expression, and assessed the association between their expression and survival.ResultsMost EMPD lesions (108/110, 98.2%) were positive for CDK4 staining and there was a positive correlation between CDK4 expression and cyclin D1 expression (r = 0.54, p < 0.001). Tumor thickness (p = 0.0003) and the presence of regional lymph node metastasis (p = 0.015) were significantly associated with high CDK4 expression. Regarding invasive EMPD, the multivariate analysis did not show the correlation between the expression of CDK4/cyclin D1 and survival outcomes (HR: 3.14, p = 0.14).ConclusionThe overexpression of CDK4 was identified as a major risk factor for disease progression. CDK4-targeted therapy could thus be a novel treatment option for unresectable EMPD.

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“…rough whole-exome sequencing, Zhang et al [4,5] revealed the full genomic mutational profiles of EMPD, demonstrating that KMT2C, ARID2, and FOXA1 mutations were frequent in EMPD, and other driver gene mutations, such as those in PIK3CA, KRAS, BRAF, and AKT1, have also been reported [6].…”

Section: Introductionmentioning

confidence: 99%

Detection of MSH2 Gene Methylation in Extramammary Paget’s Disease by Methylation-Sensitive High-Resolution Melting Analysis

Liu

Zhu

Wu³

et al. 2021

Journal of Oncology

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Background. Extramammary Paget’s disease (EMPD) is a rare skin tumor. Hypermethylation in the MSH2 promoter resulting in the downregulation of its protein expression shows a high detection rate in EMPD tumor tissue, which indicates that the methylation of MSH2 may play an important role in the pathogenesis of EMPD. Objective. This study aims to establish a rapid analysis strategy based on the methylation-sensitive high-resolution melting curve (MS-HRM) to detect the methylation level of the MSH2 promoter. Methods. With the use of universal methylated human DNA products, we established the MS-HRM standard curve to quantitatively detect the methylation level of the MSH2 promoter. Then, all 57 EMPD tumor DNA samples were analyzed. Pyrosequencing assay was also carried out to test the accuracy and efficacy of MS-HRM. Besides, a total of 54 human normal and other cancerous tissues were included in this study to test the reliability and versatility of the MS-HRM standard curve. Results. In this study, by using the established MS-HRM, we found that 96.5% (55/57) EMPD tumor samples had varying methylation levels in the MSH2 promoter ranging from 0% to 30%. Then, the methylation data were compared to the results obtained from pyrosequencing, which showed a high correlation between these two techniques by Pearson’s correlation (r = 0.9425) and Bland–Altman plots (mean difference = −0.1069) indicating that the methylation levels analyzed by MS-HRM were consistent with DNA pyrosequencing. Furthermore, in 23 normal and 31 other cancerous tissue samples, there were two colorectal cancer (CRC) tissues that tested MSH2 methylation positive (1% and 5%) which confirmed that our established MS-HRM can be widely applied to various types of samples. Conclusion. MS-HRM standard curve can be used for the detection of the methylation level of MSH2 in EMPD tumor samples and other cancerous tissues potentially, which presents a promising candidate as a quantitative assay to analyze MSH2 promoter methylation in routine pathological procedure.

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Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease

Cited by 17 publications

References 29 publications

Extramammary Paget’s Disease: Diagnosis, Pathogenesis, and Treatment with Focus on Recent Developments

Extramammary Paget’s Disease: Diagnosis, Pathogenesis, and Treatment with Focus on Recent Developments

CDK4: A Novel Therapeutic Target for Extramammary Paget’s Disease

Detection of MSH2 Gene Methylation in Extramammary Paget’s Disease by Methylation-Sensitive High-Resolution Melting Analysis

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