期刊
CLINICAL CANCER RESEARCH
卷 28, 期 5, 页码 928-938出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-21-3762
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资金
- Department of Defense [W81XWH-14-2-0183]
- PhRMA Foundation
- Kure It Cancer Research Foundation
- Natural Sciences and Engineering Research Council of Canada
- Pacific Northwest Prostate Cancer SPORE [P50CA97186]
- Department of Defense Prostate Cancer Biorepository Network [W81XWH-14-2-0183]
- National Cancer Institute [P01 CA163227, 5R37CA241486]
- Prostate Cancer Foundation
- Institute for Prostate Cancer Research
- Richard M. Lucas Foundation
- DFCI Medical Oncology grant award
- Claudia Adams Barr Program for Innovative Cancer Research
- H.L. Snyder Medical Research Foundation
- Cutler Family Fund for Prevention and Early Detection
This study reports a novel tissue-informed epigenetic approach for noninvasive detection of neuroendocrine prostate cancer (NEPC) in men with advanced prostate cancer. The results demonstrate that the method can accurately discriminate between NEPC and CR-PRAD with high sensitivity and specificity.
Purpose Neuroendocrine prostate cancer (NEPC) is a resistance phenotype that emerges in men with metastatic castration-resistant prostate adenocarcinoma (CR-PRAD) and has important clinical implications, but is challenging to detect in practice. Herein, we report a novel tissue-informed epigenetic approach to noninvasively detect NEPC. Experimental Design: We first performed methylated immunoprecipitation and high-throughput sequencing (MeDIP-seq) on a training set of tumors, identified differentially methylated regions between NEPC and CR-PRAD, and built a model to predict the presence of NEPC (termed NEPC Risk Score). We then performed MeDIP-seq on cell-free DNA (cfDNA) from two independent cohorts of men with NEPC or CR-PRAD and assessed the accuracy of the model to predict the presence NEPC. Results: The test cohort comprised cfDNA samples from 48 men, 9 with NEPC and 39 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P = 4.3 x 10(-7)) and discriminated between NEPC and CR-PRAD with high accuracy (AUROC 0.96). The optimal NEPC Risk Score cutoff demonstrated 100% sensitivity and 90% specificity for detecting NEPC. The independent, multi-institutional validation cohort included cfDNA from 53 men, including 12 with NEPC and 41 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P = 7.5 x 10(-)(12)) and perfectly discriminated NEPC from CR-PRAD (AUROC 1.0). Applying the predefined NEPC Risk Score cutoff to the validation cohort resulted in 100% sensitivity and 95% specificity for detecting NEPC. Conclusions: Tissue-informed cfDNA methylation analysis is a promising approach for noninvasive detection of NEPC in men with advanced prostate cancer.
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