Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease

Kang, Zhihua; Xu, Feng; Zhang, Qiao-An; Lin, Juan; Wu, Zhiyuan; Zhang, Xinju; Luo, Yan; Xu, Jianmin; Guan, Ming

doi:10.1038/modpathol.2012.65

Cited by 19 publications

(14 citation statements)

References 43 publications

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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%

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%

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

et al. 2020

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“…Thus our knowledge of the genetic features of EMPD remains limited. Previously, we reported the link between DLC1 methylation and PIK3CA mutation based on a correlation study and implicated that the genetic and epigenetic alterations may play a key role in determining the clinical and pathological features of EMPD 17. Herein, EMPD tumor samples from 144 unrelated patients were collected over a six years period for mutational analysis, and the demographic and clinical information for each of these patients was available, making this study the most comprehensive molecular analysis of EMPD to date.…”

Section: Discussionmentioning

confidence: 99%

“…This study is largely based on the series of EMPD skin lesions and matched normal skin tissues previously reported by our group 17. Updated clinical information was obtained from cancer registry files (Dermatology department of Huashan Hospital, Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

Oncogenic mutations in extramammary Paget's disease and their clinical relevance

Kang

Zhang

et al. 2012

Intl Journal of Cancer

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Extramammary Paget's disease (EMPD) is a rare cutaneous malignant neoplasm. The genetic alterations underlying its pathogenesis have less been described. Therefore, we analyzed the possible mutations in the KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, PIK3CA, AKT1, CTNNB1 and APC genes as well as methylation and expression of CDH1 in 144 EMPD cases and 42 matched normal skin tissues. A distinct mutation profile was identified in EMPDs with 27 (19%) cases mutant for RAS and RAF genes and 50 (35%) cases harboring oncogenic mutations in PIK3CA and AKT1. Moreover, a mutually exclusive pattern was observed in the genetic variants in these two signaling pathways. No mutation was detected in CTNNB1 and APC genes. High prevalence of low expression and hypermethylation of CDH1 gene was detected in 33 and 48% of the EMPD cases, respectively. Furthermore, PIK3CA and AKT1 mutations were significantly correlated with CDH1 hypermethylation which could explain why the majority of EMPD cases with mutant PIK3CA and AKT1 were invasive. Our study demonstrates that genetic variants associated with constitutive activation of RAS/RAF and PI3K/AKT pathways are involved in the pathogenesis of EMPD. This may represent novel therapeutic targets for this skin cancer.

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“…In this study, we confirmed that the extensive DLC-1 methylation was associated with the KRAS mutations in CRCs but not in adenomas. Our previous study showed that DLC-1 methylation significantly correlated with PIK3CA mutations in Paget's disease [25]. These findings highlighted the interaction between genetic and epigenetic alterations in CRC, although the mechanism underlying this phenomenon requires further study.…”

Section: Discussionmentioning

confidence: 79%

Downregulation ofDLC-1Gene by Promoter Methylation during Primary Colorectal Cancer Progression

Peng¹,

Long

et al. 2013

BioMed Research International

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Purpose. DLC-1 is a tumor suppressor gene frequently silenced in human cancers. However, the pathogenicity of DLC-1 epigenetic silencing in the mucosa-adenoma-carcinoma transformation process of colorectal cancer (CRC) has not been studied. Methods. Promoter methylation status of DLC-1 was evaluated in 4 human CRC cell lines, 48 normal mucosa, 57 adenomas, and 80 CRC tissues with methylation-sensitive high-resolution melting analysis (MS-HRMA), while the mRNA expression was examined by qPCR. HRMA was utilized to detect the KRAS codon 12, 13 and BRAF V600Emutations. Results. Partial (1%–10%) and extensive (10%–100%) DLC-1 promoter methylations were observed in 10% and 0% of normal mucosa, 46% and 14% of adenomas, and 60% and 36% of CRCs, respectively. The promoter methylation of DLC-1 was related with the reduction of gene expression and the advanced Duke's stages (Stage C and D). DLC-1 promoter methylation and KRAS mutations are common concurrent pathological alternations. Conclusions. Epigenetic alternation plays a key role in the transcriptional silencing of DLC-1. It is also an independent risk factor related to the carcinogenesis of colorectal tumors and spans over its pathogenesis process. Therefore, DLC-1 promoter methylation quantitation may have a promising significance in the evaluation and management of CRC patients.

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Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease

Cited by 19 publications

References 43 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

Oncogenic mutations in extramammary Paget's disease and their clinical relevance

Downregulation ofDLC-1Gene by Promoter Methylation during Primary Colorectal Cancer Progression

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