Dataset Information

Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation.

ABSTRACT: Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma cell-free DNA (cfDNA). The assay quantifies tumor content and provides a phenotype evidence score that captures diverse CRPC phenotypes, leveraging regions to inform transcriptional state. We tested the design in independent clinical cohorts (n = 222 plasma samples) and qualified it achieving an AUC > 0.93 for detecting pathology-confirmed CRPC-NE (n = 136). Methylation-defined cfDNA tumor content was associated with clinical outcomes in two prospective phase II clinical trials geared towards aggressive variant CRPC and CRPC-NE. These data support the application of targeted DNA methylation for CRPC-NE detection and patient stratification.

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Neuroendocrine prostate cancer is an aggressive subtype of treatment-resistant prostate cancer. Early detection is important, but the diagnosis currently relies on metastatic biopsy. We describe the development and validation of a plasma cell-free DNA targeted methylation panel that can quantify tumor fraction and identify patients with neuroendocrine prostate cancer noninvasively. This article is featured in Selected Articles from This Issue, p. 384.

SUBMITTER: Franceschini GM

PROVIDER: S-EPMC10905672 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation.

Franceschini Gian Marco GM Quaini Orsetta O Mizuno Kei K Orlando Francesco F Ciani Yari Y Ku Sheng-Yu SY Sigouros Michael M Rothmann Emily E Alonso Alicia A Benelli Matteo M Nardella Caterina C Auh Joonghoon J Freeman Dory D Hanratty Brian B Adil Mohamed M Elemento Olivier O Tagawa Scott T ST Feng Felix Y FY Caffo Orazio O Buttigliero Consuelo C Basso Umberto U Nelson Peter S PS Corey Eva E Haffner Michael C MC Attard Gerhardt G Aparicio Ana A Demichelis Francesca F Beltran Himisha H

Cancer discovery 20240301 3

Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma c ...[more]

PMID: 38197680

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Project description:BackgroundAberrant embryo implantation and suboptimal placentation can lead to (severe) complications such as preeclampsia and fetal growth restriction later in pregnancy. Current identification of high-risk pregnancies relies on a combination of risk factors, biomarkers, and ultrasound examinations, a relatively inaccurate approach. Previously, aberrant DNA methylation due to placental hypoxia has been identified as a potential marker of placental insufficiency and, hence, potential (future) pregnancy complications. The goal of the Early Prediction of prEgnancy Complications Testing, or the ExPECT study, is to validate a genome-wide, cell-free DNA (cfDNA) methylation strategy to diagnose preeclampsia accurately. More importantly, the predictive potential of this strategy is also explored to reliably identify high-risk pregnancies early in gestation. Furthermore, a longitudinal study was conducted, including sequential blood samples from pregnant individuals experiencing both uneventful and complicated gestations, to assess the methylation dynamics of cfDNA throughout these pregnancies. A significant strength of this study is its enzymatic digest, which enriches CpG-rich regions across the genome without the need for proprietary reagents or prior selection of regions of interest. This makes it useful for the cost-effective discovery of novel markers.ResultsInvestigation of methylation patterns throughout pregnancy showed different methylation trends between unaffected and affected pregnancies. We detected differentially methylated regions (DMRs) in pregnancies complicated with preeclampsia as early as 12 weeks of gestation, with distinct differences in the methylation profile between early and late pregnancy. Two classification models were developed to diagnose and predict preeclampsia, demonstrating promising results on a small set of validation samples.ConclusionsThis study offers valuable insights into methylation changes at specific genomic regions throughout pregnancy, revealing critical differences between normal and complicated pregnancies. The power of noninvasive cfDNA methylation profiling was successfully proven, suggesting the potential to integrate this noninvasive approach into routine prenatal care.

Dataset Information

Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation.

Significance

Publications

Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation.

Similar Datasets

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