Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies

Oda, Katsutoshi; Ikeda, Yuji; Kashiyama, Tomoko; Miyasaka, Aki; Inaba, Kanako; Fukuda, Tomohiko; Asada, Kenichi; Sone, Kenbun; Wada-Hiraike, Osamu; Kawana, Kei; Osuga, Yutaka; Fujii, Tomoyuki

doi:10.1111/jog.13018

Cited by 17 publications

(5 citation statements)

References 46 publications

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“…In vitro therapeutic studies on OCCC recently supported that the PI3K/mTOR inhibitor combination significantly and specifically decreased cell proliferation and focal adhesion in OCCC, and might be a promising treatment strategy for this cancer. 24,25 Offering family genetic testing to relatives of the proband and subsequently setting up personalized medical management is a critical component of cancer genetic counseling. Interestingly, the CS diagnosis in our patient's family supposedly had been identified previously, but the patient was not given clear and actionable information about it.…”

Section: Discussionmentioning

confidence: 99%

Ovarian Clear Cell Carcinoma in Cowden Syndrome

Yauy¹,

Imbert‐Bouteille²,

Bubien³

et al. 2019

J Natl Compr Canc Netw

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This report presents the case of a 28-year-old woman diagnosed with a left adnexal mass in the context of pelvic pain that appeared 2 months earlier. First ultrasonography revealed a 4-cm pelvic mass suspected to be a uterine fibroid. Pelvic MRI showed a 10-cm left adnexal mass with a polylobed aspect, associated with a cystic portion that had a mucinous borderline epithelial part. The patient's CA 125 level was 237 UI/mL and carcinoembryonic antigen level was 37.6 ng/mL.

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Section: Discussionmentioning

confidence: 99%

Ovarian Clear Cell Carcinoma in Cowden Syndrome

Yauy¹,

Imbert‐Bouteille²,

Bubien³

et al. 2019

J Natl Compr Canc Netw

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“…Gingival biopsy was performed on the mesial papilla of the right upper lateral incisor which was the most budding and erythematous area. Genetic analysis was carried out on the PIK3CA gene by a next-generation sequencing process with confirmation of the variants by the Sanger method [ 5 ].…”

Section: Case Seriesmentioning

confidence: 99%

Gingival Biopsy to Detect Mosaicism in Overgrowth Syndromes: Report of Two Cases of Megalencephaly-Capillary Malformation Syndrome with Periodontal Anomalies

Marty

Bonnaud

Jones

et al. 2020

Case Reports in Dentistry

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Background. Megalencephaly-capillary malformation (MCAP) is a rare overgrowth syndrome caused by postzygotic activating mutations in the PIK3CA gene. Aim. To illustrate the benefits of gingival biopsy in the genetic diagnosis of overgrowth syndromes. Design. Gingival biopsy was performed on a 13-year-old patient and a 16-year-old patient with MCAP and who suffered from periodontal disease. PIK3CA sequencing was performed on DNA extracted from gingival biopsies, blood, and saliva. Results. Pathogenic p.Glu365Lys and p.Glu545Asp PIK3CA mutations were found in the gingival biopsies with an allelic frequency of 22% and 35%, respectively, while they were undetectable in blood or saliva. The genetic diagnosis of MCAP through detection of PIK3CA somatic mosaicism in a periodontal biopsy is unprecedented. Conclusions. Considering the tissue distribution and level of somatic mosaicism for PIK3CA mutation, the composite embryologic origin of periodontium and its high fibroblast cell content make it an ideal target for molecular analysis in overgrowth syndromes, and multidisciplinary approach including paediatric dentists should be encouraged. In addition, our clinical findings suggest that periodontal disease is part of the MCAP phenotypic spectrum and should be systematically investigated.

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“…OCCC is characterized by the overexpression of HNF1B [ 5 , 6 ] and is typically ER- and PR-negative. However, most HGSC cells harbor TP53 and WT-1 mutations [ 7 ]. In addition, frequent ER expression and low PR expression increase the likelihood that HGSC is hormone-dependent.…”

Section: Introductionmentioning

confidence: 99%

Exploring the cellular and molecular differences between ovarian clear cell carcinoma and high-grade serous carcinoma using single-cell RNA sequencing and GEO gene expression signatures

Guo,

Zhang,

Gao

et al. 2023

Cell Biosci

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The two most prevalent subtypes of epithelial ovarian carcinoma (EOC) are ovarian clear cell carcinoma (OCCC) and high-grade serous ovarian carcinoma (HGSC). Patients with OCCC have a poor prognosis than those with HGSC due to chemoresistance, implying the need for novel treatment target. In this study, we applied single-cell RNA sequencing (scRNA-seq) together with bulk RNA-seq data from the GEO (Gene Expression Omnibus) database (the GSE189553 dataset) to characterize and compare tumor heterogeneity and cell-level evolution between OCCC and HGSC samples. To begin, we found that the smaller proportion of an epithelial OCCC cell subset in the G2/M phase might explain OCCC chemoresistance. Second, we identified a possible pathogenic OCCC epithelial cell subcluster that overexpresses LEFTY1. Third, novel biomarkers separating OCCC from HGSC were discovered and subsequently validated on a wide scale using immunohistochemistry. Amine oxidase copper containing 1 (AOC1) was preferentially expressed in OCCC over HGSC, while S100 calcium-binding protein A2 (S100A2) was detected less frequently in OCCC than in HGSC. In addition, we discovered that metabolic pathways were enriched in the epithelial compartment of the OCCC samples. In vitro experiments verified that inhibition of oxidative phosphorylation or glycolysis pathways exerted direct antitumor effects on both OCCC and HGSC cells, while targeting glutamine metabolism or ferroptosis greatly attenuated chemosensitivity only in OCCC cells. Finally, to determine whether there were any variations in immune cell subsets between OCCC and HGSC, data from scRNA-seq and mass cytometry were pooled for analysis. In summary, our work provides the first holistic insights into the cellular and molecular distinctions between OCCC and HGSC and is a valuable source for discovering new targets to leverage in clinical treatments to improve the poor prognosis of patients with OCCC.

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Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies

Cited by 17 publications

References 46 publications

Ovarian Clear Cell Carcinoma in Cowden Syndrome

Ovarian Clear Cell Carcinoma in Cowden Syndrome

Gingival Biopsy to Detect Mosaicism in Overgrowth Syndromes: Report of Two Cases of Megalencephaly-Capillary Malformation Syndrome with Periodontal Anomalies

Exploring the cellular and molecular differences between ovarian clear cell carcinoma and high-grade serous carcinoma using single-cell RNA sequencing and GEO gene expression signatures

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