RAD51 recruitment but not replication fork stability associates with PARP inhibitor response in ovarian cancer patient-derived xenograft models.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat mutant cancers. Although PARPi sensitivity has been attributed to homologous recombination (HR) defects, other roles of HR factors have also been linked to response to PARPi, including replication fork protection. In this study, we investigated PARPi sensitivity in ovarian cancer patient-derived xenograft (PDX) models in relation to HR proficiency and replication fork protection.

Evaluation of the recently established Dutch nationwide Archipelago of Ovarian Cancer Research biobank.

Fundamental and translational research in ovarian cancer aims to enhance understanding of disease mechanisms and improve treatment and survival outcomes. To support this, we established the Dutch multicenter, interdisciplinary Archipelago of Ovarian Cancer Research (AOCR) infrastructure, which includes a nationwide biobank. In this study, we share our experiences in establishing the infrastructure, offer guidance for similar initiatives, and evaluate the AOCR patient cohort.

B cells critical for outcome in high grade serous ovarian carcinoma.

Recent work has shown evidence for the prognostic significance of tumor infiltrating B cells (B-TIL) in high grade serous ovarian carcinoma (HGSOC), the predominant histological subtype of ovarian cancer. However, it remains unknown how the favorable prognosis associated with B-TIL relates to the current standard treatments of primary debulking surgery (PDS) followed by chemotherapy or (neo-)adjuvant chemotherapy (NACT) combined with interval debulking surgery. To address this, we analyzed the prognostic impact of B-TIL in relationship to primary treatment and tumor infiltrating T cell status in a highly homogenous cohort of HGSOC patients.

Genome-wide DNA methylation in relation to ARID1A deficiency in ovarian clear cell carcinoma.

Background: The poor chemo-response and high DNA methylation of ovarian clear cell carcinoma (OCCC) have attracted extensive attentions. Recently, we revealed the mutational landscape of the human kinome and additional cancer-related genes and found deleterious mutations in ARID1A, a component of the SWI/SNF chromatin-remodeling complex, in 46% of OCCC patients. The present study aims to comprehensively investigate whether ARID1A loss and genome-wide DNA methylation are co-regulated in OCCC and identify putative therapeutic targets epigenetically regulated by ARID1A.

Methylation Analysis to Detect CIN3+ in High-Risk Human Papillomavirus-Positive Self-Samples From the Population-Based Cervical Cancer Screening Program.

Since 2017, a self-sampling device has been introduced to the Dutch population-based screening program to enable higher participation rates. However, routine triage cytology cannot be performed on self-sampling material. Methylation is an alternative triage method that can be performed directly on DNA extracted from self-samples.

The Information Technology (IT) Infrastructure of the Multicenter Archipelago of Ovarian Cancer Research Biobank: A Potential Blueprint for Other Biobanks.

Biobanks play a crucial role in fundamental and translational research by storing valuable biomaterials and data for future analyses. However, the design of their information technology (IT) infrastructures is often customized to specific requirements, thereby lacking the ability to be used for biobanks comprising other (types of) diseases. This results in substantial costs, time, and efforts for each new biobank project.

Impact of health-related behavioral factors on participation in a cervical cancer screening program: the lifelines population-based cohort.

Background: Regular participation in cervical cancer screening is critical to reducing mortality. Although certain sociodemographic factors are known to be associated with one-time participation in screening, little is known about other factors that could be related to regular participation. Therefore, this study evaluated the association between health-related behavioral factors and regular participation in cervical cancer screening.

Identification of a methylation panel as an alternative triage to detect CIN3+ in hrHPV-positive self-samples from the population-based cervical cancer screening programme.

Background: The Dutch population-based cervical cancer screening programme (PBS) consists of primary high-risk human papilloma virus (hrHPV) testing with cytology as triage test. In addition to cervical scraping by a general practitioner (GP), women are offered self-sampling to increase participation. Because cytological examination on self-sampled material is not feasible, collection of cervical samples from hrHPV-positive women by a GP is required.

The effect of extended participation windows on attendance at cervical cancer screening.

Research has long since confirmed the benefits of regular cervical cancer screening (CCS) worldwide. However, some developed countries have low participation rates despite well-organized screening programs. Given that studies in Europe typically define participation in 12-month windows from an invitation, we evaluated both whether extending this defined time window could reveal the true participation rate and how sociodemographic determinants affect participation delays.

Establishment of the Dutch Nationwide, Interdisciplinary Infrastructure and Biobank for Fundamental and Translational Ovarian Cancer Research: Archipelago of Ovarian Cancer Research.

Objectives: Ovarian cancer has the worst overall survival rate of all gynecologic malignancies. For the majority of patients, the 5-year overall survival rate of less than 50% has hardly improved over the last decades. To improve the outcome of patients with all subtypes of ovarian cancer, large-scale fundamental and translational research is needed.

NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition.

Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian cancer with high fatality rates in advanced stages due to its chemoresistant properties. LGSOC is characterized by activation of MAPK signaling, and recent clinical trials indicate that the MEK inhibitor (MEKi) trametinib may be a good treatment option for a subset of patients. Understanding MEKi-resistance mechanisms and subsequent identification of rational drug combinations to suppress resistance may greatly improve LGSOC treatment strategies.

Preferences and Experiences Regarding the Use of the Self-Sampling Device in hrHPV Screening for Cervical Cancer.

Background: To improve participation in the Dutch cervical cancer screening, a self-sampling device (SSD) was introduced in 2017 into the Dutch population-based screening programme (PBS) for the early detection of cervical cancer. The aim of this study was to gather potential preferences and experiences that might influence a woman's decision to use the SSD in the Dutch PBS.

Methods: A scoping review was performed in the PubMed database.

Prognostic image-based quantification of CD8CD103 T cell subsets in high-grade serous ovarian cancer patients.

CD103-positive tissue resident memory-like CD8 T cells (CD8CD103 TRM) are associated with improved prognosis across malignancies, including high-grade serous ovarian cancer (HGSOC). However, whether quantification of CD8, CD103 or both is required to improve existing survival prediction and whether all HGSOC patients or only specific subgroups of patients benefit from infiltration, remains unclear. To address this question, we applied image-based quantification of CD8 and CD103 multiplex immunohistochemistry in the intratumoral and stromal compartments of 268 advanced-stage HGSOC patients from two independent clinical institutions.

DNA methylation markers as triage test for the early identification of cervical lesions in a Chinese population.

Objective strategies are required in cervical cancer screening. We have identified several DNA methylation markers with high sensitivity and specificity to detect cervical intraepithelial neoplasia 2 or worse (CIN2+) in Dutch women. Our study aims to analyze the diagnostic characteristics of these markers in a Chinese cohort.

Evaluation of six methylation markers derived from genome-wide screens for detection of cervical precancer and cancer.

To evaluate the triage performance of six host-cell DNA methylation markers derived from two genome-wide discovery screens for detection of cervical precancer (cervical intraepithelial neoplasia 3 [CIN]) and cancer. Human papillomavirus-positive cervical scrapes of controls (≤CIN1; n = 352) and women diagnosed with CIN3 (n = 175) or cervical cancer (n = 50) were analyzed for methylation of , , , , and . Methylation levels increased significantly with disease severity (all markers p < 0.

Kinome capture sequencing of high-grade serous ovarian carcinoma reveals novel mutations in the JAK3 gene.

High-grade serous ovarian carcinoma (HGSOC) remains the deadliest form of epithelial ovarian cancer and despite major efforts little improvement in overall survival has been achieved. Identification of recurring "driver" genetic lesions has the potential to enable design of novel therapies for cancer. Here, we report on a study to find such new therapeutic targets for HGSOC using exome-capture sequencing approach targeting all kinase genes in 127 patient samples.

Low-dose triple drug combination targeting the PI3K/AKT/mTOR pathway and the MAPK pathway is an effective approach in ovarian clear cell carcinoma.

Advanced stage ovarian clear cell carcinoma (OCCC) is poorly responsive to platinum-based chemotherapy and has an unfavorable prognosis. Previous studies revealed heterogeneous mutations in PI3K/AKT/mTOR and MAPK pathway nodules converging in mTORC1/2 activation. Here, we aimed to identify an effective low-dose combination of PI3K/AKT/mTOR pathway and MAPK pathway inhibitors simultaneously targeting key kinases in OCCC to preclude single-inhibitor initiated pathway rewiring and limit toxicity.

DNA methylation markers as a triage test for identification of cervical lesions in a high risk human papillomavirus positive screening cohort.

Objective triage strategies are required to prevent unnecessary referrals for colposcopy in population-based screening programs using primary high-risk human papillomavirus (hrHPV) testing. We have identified several DNA methylation markers with high sensitivity and specificity for detection of high-grade cervical intraepithelial neoplasia or worse (CIN2+) in women referred for colposcopy. Our study assessed diagnostic potential of these methylation markers in a hrHPV-positive screening cohort.

Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer.

Cervical cancer development following a persistent infection with high-risk human papillomavirus (hrHPV) is driven by additional host-cell changes, such as altered DNA methylation. In previous studies, we have identified 12 methylated host genes associated with cervical cancer and pre-cancer (CIN2/3). This study systematically analyzed the onset and DNA methylation pattern of these genes during hrHPV-induced carcinogenesis using a longitudinal in vitro model of hrHPV-transformed cell lines (n = 14) and hrHPV-positive cervical scrapings (n = 113) covering various stages of cervical carcinogenesis.

ARID1A mutant ovarian clear cell carcinoma: A clear target for synthetic lethal strategies.

SWI/SNF chromatin remodeling complexes play an important role in the epigenetic regulation of chromatin structure and gene transcription. Mutual exclusive subunits in the SWI/SNF complex include the DNA targeting members ARID1A and ARID1B as well as the ATPases SMARCA2 and SMARCA4. SWI/SNF complexes are mutated across many cancer types.

HER2 immunohistochemistry in endometrial and ovarian clear cell carcinoma: discordance between antibodies and with in-situ hybridisation.

Aims: Treatment with anti-HER2 therapy could be beneficial for patients with HER2-positive endometrial and ovarian clear cell carcinoma (CCC). We studied HER2 overexpression by immunohistochemistry (IHC) using three different antibodies, including concordance with amplification by in-situ hybridisation (ISH).

Methods And Results: IHC and ISH were performed on tissue microarrays of 101 tumours: 58 endometrial pure CCC, 19 endometrial mixed carcinomas with a CCC component and 24 ovarian pure CCC.

Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1.

Many epigenetically inactivated genes involved in ovarian cancer (OC) development and progression remain to be identified. In this study we undertook an integrated approach that consisted of identification of genome-wide expression patterns of primary OC samples and normal ovarian surface epithelium along with a pharmacologic unmasking strategy using 3 OC and 3 immortalized normal ovarian epithelial cell lines. Our filtering scheme identified 43 OC specific methylated genes and among the 5 top candidates (GULP1, CLIP4, BAMBI, NT5E, TGFβ2), we performed extended studies of GULP1.

ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitors.

Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome-centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines.