scholarly journals Clinical significance of metabolism-related genes and FAK activity in ovarian high-grade serous carcinoma

BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Masakazu Sato ◽  
Sho Sato ◽  
Daisuke Shintani ◽  
Mieko Hanaoka ◽  
Aiko Ogasawara ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Poor Prognosis ◽  
Medical Center ◽  
Parp Inhibitors ◽  
Serous Carcinoma ◽  
High Grade ◽  
Rna Seq ◽  
Stage Iiic ◽  
Free Survival ◽  
Medical University

Abstract Background Administration of poly (ADP-ribose) polymerase (PARP) inhibitors after achieving a response to platinum-containing drugs significantly prolonged relapse-free survival compared to placebo administration. PARP inhibitors have been used in clinical practice. However, patients with platinum-resistant relapsed ovarian cancer still have a poor prognosis and there is an unmet need. The purpose of this study was to examine the clinical significance of metabolic genes and focal adhesion kinase (FAK) activity in advanced ovarian high-grade serous carcinoma (HGSC). Methods The RNA sequencing (RNA-seq) data and clinical data of HGSC patients were obtained from the Genomic Data Commons (GDC) Data Portal and analysed (https://portal.gdc.cancer.gov/). In addition, tumour tissue was sampled by laparotomy or screening laparoscopy prior to treatment initiation from patients diagnosed with stage IIIC ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) classification, 2014) at the Saitama Medical University International Medical Center, and among the patients diagnosed with HGSC, 16 cases of available cryopreserved specimens were included in this study. The present study was reviewed and approved by the Institutional Review Board of Saitama Medical University International Medical Center (Saitama, Japan). Among the 6307 variable genes detected in both The Cancer Genome Atlas-Ovarian (TCGA-OV) data and clinical specimen data, 35 genes related to metabolism and FAK activity were applied. RNA-seq data were analysed using the Subio Platform (Subio Inc, Japan). JMP 15 (SAS, USA) was used for statistical analysis and various types of machine learning. The Kaplan-Meier method was used for survival analysis, and the Wilcoxon test was used to analyse significant differences. P < 0.05 was considered significant. Results In the TCGA-OV data, patients with stage IIIC with a residual tumour diameter of 1-10 mm were selected for K means clustering and classified into groups with significant prognostic correlations (p = 0.0444). These groups were significantly associated with platinum sensitivity/resistance in clinical cases (χ2 test, p = 0.0408) and showed significant relationships with progression-free survival (p = 0.0307). Conclusion In the TCGA-OV data, 2 groups classified by clustering focusing on metabolism-related genes and FAK activity were shown to be associated with platinum resistance and a poor prognosis.

scholarly journals Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 547
Author(s):  
Iolia Akaev ◽  
Siavash Rahimi ◽  
Olubukola Onifade ◽  
Francis John Edward Gardner ◽  
David Castells-Rufas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Unknown Origin ◽  
Parp Inhibitors ◽  
Serous Carcinoma ◽  
High Grade ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Epithelial Cancers ◽  
Pathogenic Variants ◽  
Pathogenic Mutations

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

scholarly journals Up-Regulation of HDAC6 Results in Poor Prognosis and Chemoresistance in Patients with Advanced Ovarian High-Grade Serous Carcinoma

2020 ◽  
Author(s):  
Mitsutake Yano ◽  
Mariko Miyazawa ◽  
Naoki Ogane ◽  
Aiko Ogasawara ◽  
Kosei Hasegawa ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Poor Prognosis ◽  
Hypoxia Inducible Factor ◽  
Progression Free Survival ◽  
Clinicopathological Characteristics ◽  
Serous Carcinoma ◽  
Clinical Samples ◽  
High Grade ◽  
Histone Deacetylase 6 ◽  
Free Survival

Abstract Background: Ovarian high-grade serous carcinoma (HGSC) gradually acquires chemoresistance after recurrence. In our previous study on ovarian clear cell carcinoma, histone deacetylase 6 (HDAC6) led to chemoresistance. This study aimed to evaluate HDAC6 as a predictor of chemoresistance and therapeutic target for ovarian HGSC. Methods: We evaluated the clinical significance of HDAC6 as a predictor of prognosis and chemoresistance in HGSC. Immunohistochemical expressions of HDAC6, programmed cell death ligand-1 (PD-L1), and hypoxia inducible factor-1α (HIF-1α) were analyzed using clinical samples from 88 patients with ovarian HGSC. The clinicopathological characteristics were reviewed. Results: Twenty-three patients had high HDAC6 expression; 10, positive PD-L1 expression; and 33, high HIF-1α expression. HDAC6 up-regulation was correlated with not undergoing interval debulking surgery (p < 0.001), incomplete surgical resection (p = 0.002), and frequent occurrence of stable disease/progressive disease according to the RECIST (p = 0.005) criteria. On Kaplan-Meier analysis, high HDAC6 expression was significantly associated with decreased progression-free survival (p = 0.001) and overall survival (p = 0.008). On multivariate analysis, high HDAC6 expression (hazard ratio = 1.65; 95% confidence interval 1.03–2.66, p = 0.039) and surgery status were independent prognostic factors of progression-free survival. PD-L1 and HIF-1α expressions positively correlated with HDAC6. Conclusion: HDAC6 is a potential therapeutic target since HDAC6 up-regulation might cause poor prognosis in patients with ovarian HGSC.

scholarly journals Targeting progesterone signaling prevents metastatic ovarian cancer

2020 ◽  
Vol 117 (50) ◽  
pp. 31993-32004
Author(s):  
Olga Kim ◽  
Eun Young Park ◽  
Sun Young Kwon ◽  
Sojin Shin ◽  
Robert E. Emerson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Deleterious Mutation ◽  
Peritoneal Metastases ◽  
Cancer Development ◽  
Serous Carcinoma ◽  
Cancer Type ◽  
High Grade ◽  
Primary Tumors ◽  
High Risk Populations ◽  
Genetic Deletion

Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.

scholarly journals Altered expression of different GalNAc-transferases is associated with disease progression and poor prognosis in women with high-grade serous ovarian cancer

2017 ◽  
Vol 51 (6) ◽  
pp. 1887-1897 ◽  
Author(s):  
Razan Sheta ◽  
Magdalena Bachvarova ◽  
Marie Plante ◽  
Jean Gregoire ◽  
Marie-Claude Renaud ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Disease Progression ◽  
Poor Prognosis ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Altered Expression

scholarly journals Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Carcinoma

2019 ◽  
Author(s):  
N. Tamura ◽  
N. Shaikh ◽  
D. Muliaditan ◽  
J. McGuinness ◽  
D. Moralli ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Single Molecule ◽  
Chromosomal Instability ◽  
Poor Prognosis ◽  
Spindle Assembly Checkpoint ◽  
Western World ◽  
Cancer Type ◽  
High Grade ◽  
Serous Ovarian Carcinoma

AbstractChromosomal instability (CIN), the continual gain and loss of chromosomes or parts of chromosomes, occurs in the majority of cancers and confers poor prognosis. Mechanisms driving CIN remain unknown in most cancer types due to a scarcity of functional studies. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynaecological malignancy in the Western world with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosome aberrations and knowledge of causative mechanisms is likely to represent an important step towards combating the poor prognosis of this disease. However, very little is known about the nature of chromosomal instability exhibited by this cancer type in particular due to a historical lack of appropriate cell line models. Here we perform the first in-depth functional characterisation of mechanisms driving CIN in HGSC by analysing eight cell lines that accurately recapitulate HGSC genetics as defined by recent studies. We show, using a range of established functional CIN assays combined with live cell imaging and single molecule DNA fibre analysis, that multiple mechanisms co-exist to drive CIN in HGSC. These include supernumerary centrosomes, elevated microtubule dynamics and DNA replication stress. By contrast, the spindle assembly checkpoint was intact. These findings are relevant for developing therapeutic approaches to manipulating CIN in ovarian cancer, and suggests that such approaches may need to be multimodal to combat multiple co-existing CIN drivers.

scholarly journals BRPF3 knockdown or inhibition moderately reverses olaparib resistance in high grade serous ovarian carcinoma, but depletion of H3K14 acetylation has no effect

2021 ◽  
Author(s):  
Benjamin G Bitler ◽  
Tomomi M Yamamoto ◽  
Alexandra McMellen ◽  
Hyunmin Kim ◽  
Zachary Levi Watson
Keyword(s):  
Dna Repair ◽  
Ovarian Carcinoma ◽  
Clinical Problem ◽  
Parp Inhibitors ◽  
High Grade ◽  
Rna Seq ◽  
Damage Resistance ◽  
Altered Expression ◽  
Serous Ovarian Carcinoma ◽  
H3k14 Acetylation

Background: PARP inhibitors (PARPi) kill cancer cells by stalling DNA replication and preventing DNA repair, resulting in a critical accumulation of DNA damage. Resistance to PARPi is a growing clinical problem in the treatment of high grade serous ovarian carcinoma (HGSOC). Acetylation of histone H3 lysine 14 (H3K14ac) and associated histone acetyltransferases (HATs) have known functions in DNA repair and replication, but their expression and activities have not been examined in the context of PARPi-resistant HGSOC. Results: Using mass spectrometry profiling of histone modifications, we observed altered H3K14ac enrichment in PARPi-resistant HGSOC cells relative to isogenic PARPi-sensitive lines. By RT-qPCR and RNA-Seq, we also observed altered expression of numerous HATs in PARPi-resistant HGSOC cells and a PARPi-resistant PDX model. Knockdown of HATs only modestly altered PARPi response, although knockdown and inhibition of PCAF significantly increased resistance. Pharmacologic inhibition of HBO1 severely depleted H3K14ac but did not affect PARPi response. However, knockdown and inhibition of BRPF3, which is known to interact in a complex with HBO1, did reduce PARPi resistance. Conclusions: This study demonstrates that severe depletion of H3K14ac does not affect PARPi response in HGSOC. Our data suggest that bromodomain functions of HAT proteins such as PCAF, or accessory proteins such as BRPF3, may play a greater role in PARPi response than acetyltransferase functions.

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