Genes

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Genetic Alterations and Prognosis in Extramammary Paget’s Disease

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Genetic Alterations and Prognosis in Extramammary Paget’s Disease

Extramammary Paget’s Disease (EMPD) is a relatively rare skin cancer that typically appears in genital area. As a result, little is known about the association between genetic changes and prognosis for people diagnosed with this condition. This study was conducted in Japan using a national database. This database included people who had undergone comprehensive genomic profiling tests to examine genetic changes in their cancer. We aimed to explore the relationship between specific genetic changes and the prognosis of EMPD cases. To do this, we analyzed 167 cases from the database, focusing on 127 people for whom survival data was available. Our main goal was to see how genetic alterations might impact patient survival. In our cohort, a gene called ‘CDKN2A’ was most frequently altered (56%), and we found that changes to CDKN2A (such as loss) was linked to poorer prognosis. Similarly, cases with changes to a gene called ‘BRCA2’ were also associated with a poorer prognosis. We further noted that earlier testing for genetic changes could lead to better treatment planning and outcomes. In conclusion, identifying CDKN2A genetic changes in EMPD may be related to poor prognosis. These novel findings may help doctors create more personalized treatment plans for people with EMPD. Understanding these genetic factors also opens new research opportunities in EMPD.

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Whole genome sequencing of HER2-positive metastatic extramammary Paget’s disease

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Whole genome sequencing of HER2-positive metastatic extramammary Paget’s disease

Extramammary Paget’s disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions. Here, we aim to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novometastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease landscape

A familial case of extramammary Paget disease: Analysis of whole-exome sequencing

A familial case of extramammary Paget disease: Analysis of whole-exome sequencing

Extramammary Paget disease (EMPD) is a rare, cutaneous malignancy that is most likely to occur in the genital area of the elderly population. Although there have been several reports on familial EMPD, its pathogenic germline mutations have not been analyzed. We herein report the results of the genetic analysis of an EMPD patient with a family history of the same disease, affecting her mother and sister.

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FOXM1: a new therapeutic target of extramammary Paget disease

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FOXM1: a new therapeutic target of extramammary Paget disease

Extramammary Paget disease (EMPD) is a rare skin cancer that primarily affects older individuals predominantly in areas with apocrine sweat glands. Although most early EMPD lesions are indolent, patients with metastatic EMPD have a poor prognosis due to the lack of effective systemic treatment. In this study, we investigated the role of forkhead box M1 (FOXM1), a potent transcription factor, in EMPD and assessed the potential of FOXM1 as a therapeutic target. Immunohistochemistry of 112 primary and 17 metastatic EMPD samples revealed that FOXM1 expression increased with tumor progression. Patients in whom FOXM1 was expressed in more than 10% of tumor cells had significantly shorter disease-specific survival than the other patients (p = 0.0397). In in vitro studies using our newly established EMPD cell line, KS-EMPD-1, we found high expression of FOXM1. Knockdown of FOXM1 impaired tumor cell viability, migration, and invasion. Inhibition of FOXM1 using thiostrepton also reduced tumor cell viability in a dose-dependent manner. These findings suggest that FOXM1 is a promising therapeutic target for patients with EMPD.

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Integrative bioinformatics approaches to map key biological markers and therapeutic drugs in Extramammary Paget’s disease of the scrotum

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Integrative bioinformatics approaches to map key biological markers and therapeutic drugs in Extramammary Paget’s disease of the scrotum

Extramammary Paget’s disease (EMPD) is an intra-epidermal adenocarcinoma. Till now, the mechanisms underlying the pathogenesis of scrotal EMPD is poorly known. This present study aims to explore the knowledge of molecular mechanism of scrotal EMPD by identifying the hub genes and candidate drugs using integrated bioinformatics approaches. Firstly, the microarray datasets (GSE117285) were downloaded from the GEO database and then analyzed using GEO2R in order to obtain differentially expressed genes (DEGs). Moreover, hub genes were identified on the basis of their degree of connectivity using Cytohubba plugin of cytoscape tool. Finally, GEPIA and DGIdb were used for the survival analysis and selection of therapeutic candidates, respectively. A total of 786 DEGs were identified, of which 10 genes were considered as hub genes on the basis of the highest degree of connectivity. After the survival analysis of ten hub genes, a total of 5 genes were found to be altered in EMPD patients. Furthermore, 14 drugs of CHEK1, CCNA2, and CDK1 were found to have therapeutic potential against EMPD. This study updates the information and yields a new perspective in the context of understanding the pathogenesis of EMPD. In future, hub genes and candidate drugs might be capable of improving the personalized detection and therapies for EMPD.

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A Case Report of Familial Extramammary Paget's Disease in Female Siblings

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A Case Report of Familial Extramammary Paget's Disease in Female Siblings

Extramammary Paget’s disease (EMPD) is a rare intraepithelial neoplasm that occurs in apocrine-bearing areas of skin. Most EMPD patients initially present with chronic pruritic eczematous lesions involving genitalia, perineum and perianal area. Familial form of EMPD is extremely rare. Several genetic mutations have been proposed but specific modes of inheritance are still unknown. This article reports two cases of familial extramammary Paget’s disease in female siblings.

Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget’s Disease of the Vulva

We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore.

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Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease

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Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease

Primary Extra‐mammary Paget's disease (EMPD) is a very rare cutaneous adenocarcinoma affecting anogenital or axillary regions. It is characterized by a prolonged course with recurrences and eventually distant metastatic spread for which no specific therapy is known.

Eighteen EMPD (13 vulvar and five scrotal) and ten mammary Paget's disease (MPD) cases were comprehensively profiled for gene mutations, fusions and copy number alterations, and for therapy‐relevant protein biomarkers).

Mutations in TP53 and PIK3CA were the most frequent in both cohorts: 7/15 and 5/15 in EMPD; 1/6 and 4/7 in MPD HER2 gene amplification was detected in 4/18 EMPD (3 vulvar and 1 scrotal case) in contrast to MPD where it was detected in the majority (7/8) of cases. TOP2A gene amplification was seen in 2/12 EMPD and 1/6 MPD, respectively. Similarly, no difference in estrogen receptor expression was seen between the EMPD (4/15) and MPD (3/10). Androgen receptor was also expressed in the majority of both cohorts (12/16 EMPD) and (7/8 MPD).Here ARv7 splice variant was detected in 1/7 EMPD and 1/4 MPD cases, respectively. PD‐L1 expression on immune cells was exclusively observed in three vulvar EMPD. In contrast to MPD, six EMPDs harbored a “high” tumor mutation burden (≥10 mutations/Mb). All tested cases from both cohorts were MSI stable.

Extramammary Paget disease shows differential expression of B7 family members B7-H3, B7-H4, PD-L1, PD-L2 and cancer/ testis antigens NY-ESO-1 and MAGE-A

Extramammary Paget disease shows differential expression of B7 family members B7-H3, B7-H4, PD-L1, PD-L2 and cancer/ testis antigens NY-ESO-1 and MAGE-A

Extramammary Paget disease (EMPD) is a rare cutaneous adenocarcinoma of the anogenital region most commonly treated with surgical excision. Surgical margin clearance is often problematic and recurrence rates remain high indicating the need for additional therapeutic options. Topical immunomodulators have been used with reported success suggesting EMPD may respond to other immunotherapies. This study investigates EMPD protein expression of targetable B7 family members and cancer/testis antigens (CTAs) B7-H3, B7-H4, PD-L1, PD-L2, MAGE-A, and NY-ESO-1 and components of antigen presenting machinery B2M and MHC-I.

Identification of genetic alterations in extramammary Paget disease using whole exome analysis

Identification of genetic alterations in extramammary Paget disease using whole exome analysis

Exome analysis revealed recurrent somatic mutations in several genes, including TP53, PIK3CA, and ERBB2. We identified additional candidate exons by searching the COSMIC database for exons that are frequently mutated in other adenocarcinomas. We obtained 19 exons in 12 genes as candidate exons, and performed target amplicon sequencing in samples obtained from EMPD patients. New somatic mutations in the TP53 gene were identified in six EMPD patients. Single nucleotide polymorphism analysis revealed multiple chromosomal alterations in three EMPD specimens, and two specimens exhibited amplification of chromosome 12p13 and losses of 3p21–24, 7q22 and 13q12–21.

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Methylation and expression analysis of mismatch repair genes in extramammary Paget's disease

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Methylation and expression analysis of mismatch repair genes in extramammary Paget's disease

Extramammary Paget's disease (EMPD) is a rare skin cancer with relative high frequencies of germline and somatic mismatch repair (MMR) genes mutations. However, the methylation and expression of these genes have not been validated in EMPD.

This study aims to confirm the methylation and expression of MMR genes in EMPD.

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