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

Kiniwa, Yukiko; Yasuda, Jun; Saitō, Sakae; Saito, Rumiko; Motoike, Ikuko N.; Danjoh, Inaho; Kinoshita, Kengo; Fuse, Nobuo; Yamamoto, Masayuki; Okuyama, Ryuhei

doi:10.1016/j.jdermsci.2019.03.006

Cited by 28 publications

(23 citation statements)

References 35 publications

(41 reference statements)

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“…37 Next-generation sequencing from this cohort is in line with previous studies. [41][42][43] In contrast to Kiniwa et al who reported mutations in ERBB2 gene, 43 we found only ERBB2 amplification but no pathogenic ERBB2 mutations in any of our cases.…”

Section: Discussioncontrasting

confidence: 99%

“…Next‐generation sequencing from this cohort is in line with previous studies . In contrast to Kiniwa et al who reported mutations in ERBB2 gene, we found only ERBB2 amplification but no pathogenic ERBB2 mutations in any of our cases. The presence of mutations within the PIK3CA/AKT pathway indicates a potential for targeted therapeutic trials with newer generation of PIK3CA inhibitors, either alone or in combination with other therapies .…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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Background 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. Methods 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). Results 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. Conclusions EMPD shares some targetable biomarkers with its mammary counterpart (steroid receptors, PIK3CA signaling pathways, TOP2A amplification). HER2 positivity is notably lower in EMPD while biomarkers to immune checkpoint inhibitors (high TMB and PD‐L1) were observed in some EMPD. Given that no consistent molecular alteration characterizes EMPD, comprehensive theranostic profiling is required to identify individual patients with targetable molecular alterations.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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“…Several sequencing studies using targeted or whole-exome sequencing approaches have revealed that EMPD and MPD carry driver mutations in PIK3CA, KRAS, BRAF, AKT1, and other genes [7][8][9][10]. Although the aforementioned genes are frequently mutated in various cancers [11] and are not particularly characteristic of PD, it is important to gather information on these candidate driver mutations towards understanding the underlying molecular genetic basis of EMPD.…”

Section: Introductionmentioning

confidence: 99%

Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease

Takeichi

Matsumoto

Tsunoda

et al. 2020

Cancers

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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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“…Recently, combining WES with amplicon sequencing has become an effective strategy for detecting somatic mutations in tumors, psychiatric disorders, and FCDII . To avoid false‐positive results in the WES data, we applied strict screening strategies, and we performed site‐specific amplicon sequencing for the validation.…”

Section: Discussionmentioning

confidence: 99%

Somatic variants in new candidate genes identified in focal cortical dysplasia type II

et al. 2020

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Objective: Focal cortical dysplasia type II (FCDII) is a malformation of cortex development commonly found in children with drug-resistant epilepsy. FCDII has been associated with somatic mutations in mammalian target of rapamycin (mTOR)-related pathway genes and an upregulation of mTOR. Somatic mutations were found in 10%-63% of FCDII samples; the frequency of the mutant allele was 0.93%-33.5%. This study aimed to find new candidate genes involved in FCDII. Methods: We collected resected FCD lesions, perilesional brain tissues, and peripheral blood from 17 children with pathologically confirmed FCDII. We performed whole exome sequencing and followed a set of screening and analysis strategies to identify potentially deleterious somatic variants (PDSVs) in brain-expressed genes.We performed site-specific amplicon sequencing to validate the results. We also performed an in vitro functional study on an IRS1 variant. Results: In six of 17 samples, we identified seven PDSVs in seven genes, including two frameshift variants and five missense variants. The frequencies of the variant allele were 1.29%-5.50%. The genes were MTOR, TSC2, IRS1, RAB6B, RALA, HTR6, and ZNF337. PDSVs in IRS1, RAB6B, ZNF337, RALA, and HTR6 had not been previously associated with FCD. In one lesion, two PDSVs were found in two genes. In a transfected cell line, we demonstrated that the c.1791dupG (identified in FCDII from Patient 1) led to a truncated IRS1 and significant mTOR hyperactivation compared to cells that carried wild-type IRS1. mTOR was also activated in FCDII tissue from

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

Cited by 28 publications

References 35 publications

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

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

Frequent FOXA1-Activating Mutations in Extramammary Paget’s Disease

Somatic variants in new candidate genes identified in focal cortical dysplasia type II

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