ZNFX1 functions as a master regulator of epigenetically induced pathogen mimicry and inflammasome signaling in cancer.

DNA methyltransferase and poly (ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon genes (STING)-dependent pathogen mimicry response (PMR) in ovarian and other cancers. Here, we showed that combining DNMTis and PARPis upregulates expression of the nucleic-acid sensor NFX1-type zinc finger-containing 1 protein (ZNFX1). ZNFX1 mediated induction of PMR in mitochondria, serving as a gateway for STING-dependent interferon/inflammasome signaling.

Investigating proteogenomic divergence in patient-derived xenograft models of ovarian cancer.

Within ovarian cancer research, patient-derived xenograft (PDX) models recapitulate histologic features and genomic aberrations found in original tumors. However, conflicting data from published studies have demonstrated significant transcriptional differences between PDXs and original tumors, challenging the fidelity of these models. We employed a quantitative mass spectrometry-based proteomic approach coupled with generation of patient-specific databases using RNA-seq data to investigate the proteogenomic landscape of serially-passaged PDX models established from two patients with distinct subtypes of ovarian cancer.

ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer.

DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR.

Implementation of endometrial cancer molecular subtyping into a hybrid community-academic practice.

Objectives: We sought to confirm utility of our institution's modified Proactive Molecular Risk Classifier for Endometrial Cancer protocol in our daily practice, which includes mismatch repair (MMR), p53, and L1 cell adhesion molecule (L1CAM) immunohistochemistry with in-house next-generation sequencing for POLE, TP53, and CTNNB1.

Methods: We conducted a retrospective review of all patients in our institution who underwent primary endometrial carcinoma resection from the year prior to protocol implementation (PRE; October 1, 2020, to September 30, 2021) through first year of implementation (POST; October 1, 2021, to September 30, 2022) to compare the distribution of molecular and traditional staging factors using GOG-249 criteria to assign clinical risk.

Results: In total, 136 of 260 PRE patients were classified as clinically low risk (LR), of whom 31 were MMR deficient.

The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17.

PAX8 is a master transcription factor that is essential during embryogenesis and promotes neoplastic growth. It is expressed by the secretory cells lining the female reproductive tract, and its deletion during development results in atresia of reproductive tract organs. Nearly all ovarian carcinomas express PAX8, and its knockdown results in apoptosis of ovarian cancer cells.

Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer.

Purpose: Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC.

Design: Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy.

Single-Cell RNA Sequencing of Ovarian Cancer: Promises and Challenges.

Ovarian cancer remains the leading cause of death from gynecologic malignancy in the Western world. Tumors are comprised of heterogeneous populations of various cancer, immune, and stromal cells; it is hypothesized that rare cancer stem cells within these subpopulations lead to disease recurrence and treatment resistance. Technological advances now allow for the analysis of tumor genomes and transcriptomes at the single-cell level, which provides the resolution to potentially identify these rare cancer stem cells within the larger tumor.

Multiomic Analysis of Subtype Evolution and Heterogeneity in High-Grade Serous Ovarian Carcinoma.

Multiple studies have identified transcriptome subtypes of high-grade serous ovarian carcinoma (HGSOC), but their interpretation and translation are complicated by tumor evolution and polyclonality accompanied by extensive accumulation of somatic aberrations, varying cell type admixtures, and different tissues of origin. In this study, we examined the chronology of HGSOC subtype evolution in the context of these factors using a novel integrative analysis of absolute copy-number analysis and gene expression in The Cancer Genome Atlas complemented by single-cell analysis of six independent tumors. Tumor purity, ploidy, and subclonality were reliably inferred from different genomic platforms, and these characteristics displayed marked differences between subtypes.

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

Purpose: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.

Prognostic gene expression signature for high-grade serous ovarian cancer.

Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.

Sulfated glycolipid PG545 induces endoplasmic reticulum stress and augments autophagic flux by enhancing anticancer chemotherapy efficacy in endometrial cancer.

The sulfated glycolipid PG545 shows promising antitumor activity in various cancers. This study was conducted to explore the effects and the mechanism of PG545 action in endometrial cancer (EC). PG545 exhibited strong synergy as assessed by the Chou-Talalay-Method in vitro when combined with cisplatin, or paclitaxel in both type I (Hec1B) and type II (ARK2) EC cell lines.

Molecular characterization of endometrial cancer and therapeutic implications.

Purpose Of Review: The present article reviews molecular subtyping and genomic characterization of endometrial carcinoma, and the associated therapeutic and prognostic implications.

Recent Findings: Endometrial cancer has historically been classified through histology into endometrioid and nonendometrioid subtypes with poor prognostic predictability. Molecular classification through genomic analysis now allows for a major advance in characterization.

Dilution of Molecular-Pathologic Gene Signatures by Medically Associated Factors Might Prevent Prediction of Resection Status After Debulking Surgery in Patients With Advanced Ovarian Cancer.

Purpose: Predicting surgical outcome could improve individualizing treatment strategies for patients with advanced ovarian cancer. It has been suggested earlier that gene expression signatures (GES) might harbor the potential to predict surgical outcome.

Experimental Design: Data derived from high-grade serous tumor tissue of FIGO stage IIIC/IV patients of AGO-OVAR11 trial were used to generate a transcriptome profiling.

UNC-45A is preferentially expressed in epithelial cells and binds to and co-localizes with interphase MTs.

UNC-45A is an ubiquitously expressed protein highly conserved throughout evolution. Most of what we currently know about UNC-45A pertains to its role as a regulator of the actomyosin system. However, emerging studies from both our and other laboratories support a role of UNC-45A outside of actomyosin regulation.

De novo prediction of cell-type complexity in single-cell RNA-seq and tumor microenvironments.

Recent single-cell transcriptomic studies revealed new insights into cell-type heterogeneities in cellular microenvironments unavailable from bulk studies. A significant drawback of currently available algorithms is the need to use empirical parameters or rely on indirect quality measures to estimate the degree of complexity, i.e.

Developing a Clinico-Molecular Test for Individualized Treatment of Ovarian Cancer: The interplay of Precision Medicine Informatics with Clinical and Health Economics Dimensions.

We report recent progress in the development of a precision test for individualized use of the VEGF-A targeting drug bevacizumab for treating ovarian cancer. We discuss the discovery model stage (i.e.

A patient-centered mobile health application to motivate use of genetic counseling among women with ovarian cancer: A pilot randomized controlled trial.

Objective: Despite current guidelines recommending women with ovarian cancer receive genetic risk evaluation by a genetic counselor, utilization has historically been low. We sought to assess the feasibility and effectiveness of a week-long mobile Application for Genetic Information on Cancer (mAGIC) intervention aimed to persuade women with ovarian cancer to pursue genetic counseling.

Methods: The mobile application intervention was based on the Fogg Behavior Model, and consisted of three parts: (1) identifying barriers, (2) developing motivators, and (3) providing triggers to action.

Single-cell sequencing in ovarian cancer: a new frontier in precision medicine.

Purpose Of Review: This article discusses the advances, applications and challenges of using single-cell RNA sequencing data in guiding treatment decisions for ovarian cancer.

Recent Findings: Genetic heterogeneity is a hallmark of ovarian cancer biology and underlies treatment resistance. Defining the different cell types present within a single ovarian cancer is difficult, but could ultimately lead to improvements in diagnosis and treatment.

Molecular characterization of endometrial cancer and therapeutic implications.

Purpose Of Review: The present article reviews genomic subtyping of endometrial carcinoma and new molecular markers with therapeutic and prognostic implications.

Recent Findings: Endometrial cancer has historically been classified through histology into endometrioid (type 1) and nonendometrioid (type II, mainly serous) subtypes. Molecular classification through genomic analysis now allows for a major advance in characterization; four distinct subgroups have been identified: polymerase ε (POLE) ultramutated, microsatellite unstable, copy number low/microsatellite stable, and copy number high/'serous-like'.

Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors.

It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood.

Assessment of the Intraoperative Consultation Service Rendered by General Pathologists in a Scenario Where a Well-Defined Decision Algorithm Is Followed.

Objectives: Intraoperative consultation (IOC) remains an area of general practice even within subspecialized pathology departments. This study assesses the IOCs rendered in a general pathology setting where surgeons integrate these results in a well-defined algorithm, developed with the input of specialized pathologists.

Methods: The surgical decisions to perform lymphadenectomy in patients with endometrial adenocarcinoma operated on at our institution between January 2003 and June 2015 as a result of the IOC assessment of tumor size, histologic grade, and depth of invasion in the hysterectomy specimen were analyzed.