Evidence map›Paper›PMID 41674842›Full record

ArticleResearch square2026

Integrative dual ctDNA 5mC/5hmC methylomics and clonal reconstruction infer tumor transcription and resistance phenotypes in metastatic prostate cancer.

Chennan Li, Anna Baj, Clara C Y Seo, Nicholas T Terrigino, John R Bright, S Thomas Hennigan, Isaiah M King, Scott Wilkinson, Tzu-Ting Huang, Shana Y Trostel and 6 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Research square, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0cells of the map it votes in
0citing papers in PubMed
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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Chennan LiGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
Anna BajGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.ORCID https://orcid.org/0009-0004-3636-8912
Clara C Y SeoGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
Nicholas T TerriginoGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
John R BrightGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
S Thomas HenniganGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
Isaiah M KingGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
Scott WilkinsonGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
Tzu-Ting HuangWomen's Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.ORCID https://orcid.org/0000-0002-3675-2760
Shana Y TrostelGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
William D FiggGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.ORCID https://orcid.org/0000-0003-2428-5613
William L DahutGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
David Y TakedaGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.ORCID https://orcid.org/0000-0002-5986-1169
Jung-Min LeeWomen's Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
Fatima KarzaiGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.ORCID https://orcid.org/0000-0002-3244-1332
Adam G SowalskyGenitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.ORCID https://orcid.org/0000-0003-2760-1853

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Liquid biopsies can detect actionable mutations and infer broad tumor states from genome-wide cfDNA measurements, but quantitative transcriptome-like phenotyping at single gene resolution still largely requires tissue. Here, we asked whether 6-base whole-genome sequencing that jointly quantifies 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) could infer gene expression directly from plasma. We applied this framework to plasma from patients enrolled in a phase 2 clinical trial of the PARP inhibitor olaparib plus the PD-L1 inhibitor durvalumab for metastatic castration-resistant prostate cancer. Inferred plasma transcriptomes distinguished adenocarcinoma vs. neuroendocrine phenotypes and identified a noncanonical WNT5A-associated signature linked to poor clinical response. Integrating longitudinal cfDNA methylomic profiles with phylogenetic reconstruction further revealed two resistance trajectories: one featuring high tumor heterogeneity with persistent AR signaling, and another marked by an AR-independent, stem-like program with metabolic reprogramming. These findings demonstrate that ctDNA can inform phenotype-driven tumor biology at gene-level resolution, integrating epigenetic modifications, inferred transcriptional programs, and clonal dynamics as a function of treatment response.

Identifiers

PMID41674842
PMCPMC12889828

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.