TP53 mutations in epithelial ovarian cancer

Zhang, Yu; Cao, Lan; Nguyen, Daniel; Lu, Hua

doi:10.21037/tcr.2016.08.40

Cited by 99 publications

(95 citation statements)

References 108 publications

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“…TP53 mutations were the most frequently co-occurring genomic alterations among ascites ctDNA, preoperative plasma ctDNA, and tumor DNA from EOC patients. Many studies have shown that TP53 mutations are significantly associated with EOCs because TP53 mutations are identified in 97% of the most aggressive high-grade serous ovarian carcinomas, which account for more than two-thirds of all ovarian cancers [19]. We also found that NTRK1, PIK3CA, and MYC mutations co-occurred among ascites ctDNA, preoperative plasma ctDNA, and tumor DNA from our EOC patients.…”

Section: Discussionsupporting

confidence: 58%

Clinical Implications of Circulating Tumor DNA from Ascites and Serial Plasma in Ovarian Cancer

et al. 2020

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Original ArticlePurpose The purpose of this study was to identify the clinical utility of circulating tumor DNA (ctDNA) from ascites and serial plasma samples from epithelial ovarian cancer (EOC) patients. Materials and MethodsUsing targeted next-generation sequencing, we analyzed a total of 55 EOC samples including ctDNA from ascites and serial plasma and gDNA from tumor tissues. Tumor tissues and ascites were collected during debulking surgeries and plasma samples were collected before and after the surgeries. Because one EOC patient underwent secondary debulking surgery, a total of 11 tumor tissues, 33 plasma samples, and 11 ascites samples were obtained from the 10 patients. ResultsOf the 10 patients, nine (90%) contained somatic mutations in both tumor tissues and ascites ctDNA. This mutational concordance was confirmed through correlation analysis. The mutational concordance between ascites and tumor tissues was valid in recurrent/progressive ovarian cancer. TP53 was the most frequently detected gene with mutations. ctDNA from serial plasma samples identified EOC progression/recurrence at a similar time or even more rapidly than cancer antigen 125, an established serum protein tumor marker for EOC. ConclusionOur data suggest that ascites ctDNA can be used to identify the mutational landscape of ovarian cancer for therapeutic strategy planning.

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Section: Discussionsupporting

confidence: 58%

Clinical Implications of Circulating Tumor DNA from Ascites and Serial Plasma in Ovarian Cancer

et al. 2020

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“…As it is unknown whether the ability of detached HGSC cells to colonize serous membranes might be linked to newly acquired genetic alterations, we per- mutations were found in 9 of 10 patients [56]. Likewise, ADAMTS8 was altered by SNVs in the majority of patients (6/10; in 3 cases simultaneously at 2 different sites), while 8 other loci were affected in a smaller subset of patients (1-5 out of 10).…”

Section: Genetic Alterations In Hgsc Metastasis and Spheroidsmentioning

confidence: 94%

Upregulation of mesothelial genes in ovarian carcinoma cells is associated with an unfavorable clinical outcome and the promotion of cancer cell adhesion

et al. 2020

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A hallmark of ovarian high‐grade serous carcinoma (HGSC) is its early and massive peritoneal dissemination via the peritoneal fluid. It is generally believed that tumor cells must breach the mesothelium of peritoneal organs to adhere to the underlying extracellular matrix (ECM) and initiate metastatic growth. However, the molecular mechanisms underlying these processes are only partially understood. Here, we have analyzed 52 matched samples of spheroids and solid tumor masses (suspected primary lesions and metastases) from 10 patients by targeted sequencing of 21 loci previously proposed as targets of HGSC driver mutations. This analysis revealed very similar patterns of genetic alterations in all samples. One exception was FAT3 with a strong enrichment of mutations in metastases compared with presumed primary lesions in two cases. FAT3 is a putative tumor suppressor gene that codes for an atypical cadherin, pointing a potential role in peritoneal dissemination in a subgroup of HGSC patients. By contrast, transcriptome data revealed clear and consistent differences between tumor cell spheroids from ascites and metastatic lesions, which were mirrored by the in vitro adherence of ascites‐derived spheroids. The adhesion‐induced transcriptional alterations in metastases and adherent cells resembled epithelial–mesenchymal transition, but surprisingly also included the upregulation of a specific subset of mesothelial genes, such as calretinin (CALB2) and podoplanin (PDPN). Consistent with this finding, calretinin staining was also observed in subsets of tumor cells in HGSC metastases, particularly at the invasive tumor edges. Intriguingly, a high expression of either CALB2 or PDPN was strongly associated with a poor clinical outcome. siRNA‐mediated CALB2 silencing triggered the detachment of adherent HGSC cells in vitro and inhibited the adhesion of detached HGSC cells to collagen type I. Our data suggest that the acquisition of a mesenchymal–mesothelial phenotype contributes to cancer cell adhesion to the ECM of peritoneal organs and HGSC progression.

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“…To understand the therapeutic potential of a protein target, there must be an appreciation of the underlying genetic abnormalities specific to the cancer type. The TP53 gene (tumor suppressor p53) is the most commonly mutated gene in all ovarian cancers and is especially a prognostic marker of HGSOC (80). In contrast, CCOC typically has a wild type TP53 and mutations in the tumor suppressor ARID1A (81).…”

Section: Targeting Apkcs In Ccocmentioning

confidence: 99%

The Atypical Protein Kinase C Small Molecule Inhibitor ζ-Stat, and Its Effects on Invasion Through Decreases in PKC-ζ Protein Expression

et al. 2020

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Ovarian cancer is estimated to reach 22,530 diagnoses and cause 13,980 cancer deaths per year. The most common histology diagnosed of ovarian cancer is epithelial ovarian carcinomas (EOC). An aggressive epithelial subtype is clear cell ovarian carcinoma (CCOC) and is characterized as a non-serous ovarian cancer. Protein kinase C (PKC) is an enzymatic family of proteins that have been found to be a component in cancer progression, tissue invasion, and metastasis. The atypical PKC (aPKC) isoforms, PKC-ι and PKC-ζ, have been suggested to participate in the increased proliferation of ovarian cancers. Previous studies have indicated that novel aPKC inhibitors ICA-1S and ζ-Stat decreased the migratory behaviors of colorectal cancer cells and were selective for PKC-ι/λ and PKC-ζ, respectively. The aims of this investigation were to further determine the binding mechanisms of ζ-Stat, expand on the tissue range of these compounds, investigate the therapeutic potential of ζ-Stat in CCOC, and to illustrate the disruption of invasion via the PKC-ζ signaling cascade. The methods utilized were molecular docking and virtual target screening, Western blot analysis, end-point PCR, GST pull down, cell viability and invasion and migration assays. We discovered that the small molecule inhibitor, ζ-Stat, is a prospective drug candidate to investigate as a novel potential treatment for CCOC. We also found that the PKC-ζ/Ect2/Rac1 activation pathway was decreased by ζ-Stat, which in turn decreased invasive behavior of CCOC.

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TP53 mutations in epithelial ovarian cancer

Cited by 99 publications

References 108 publications

Clinical Implications of Circulating Tumor DNA from Ascites and Serial Plasma in Ovarian Cancer

Clinical Implications of Circulating Tumor DNA from Ascites and Serial Plasma in Ovarian Cancer

Upregulation of mesothelial genes in ovarian carcinoma cells is associated with an unfavorable clinical outcome and the promotion of cancer cell adhesion

The Atypical Protein Kinase C Small Molecule Inhibitor ζ-Stat, and Its Effects on Invasion Through Decreases in PKC-ζ Protein Expression

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