Supplementary Figure S8 from Genomic and Epigenomic Analysis of Plasma Cell-Free DNA Identifies Stemness Features Associated with Worse Survival in Lethal Prostate Cancer

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posted on 2025-01-06, 08:20 authored by Pradeep S. Chauhan, Irfan Alahi, Savar Sinha, Elisa M. Ledet, Ryan Mueller, Jessica Linford, Alexander L. Shiang, Jace Webster, Lilli Greiner, Breanna Yang, Gabris Ni, Ha X. Dang, Debanjan Saha, Ramandeep K. Babbra, Wenjia Feng, Peter K. Harris, Faridi Qaium, Dzifa Y. Duose, Sanchez E. Alexander, Alexander D. Sherry, Ellen B. Jaeger, Patrick J. Miller, Sydney A. Caputo, Jacob J. Orme, Fabrice Lucien, Sean S. Park, Chad Tang, Russell K. Pachynski, Oliver Sartor, Christopher A. Maher, Aadel A. Chaudhuri

Supplementary Figure S8. Transcription factor analysis in localized prostate cancer versus blood. Log2 fold change of the 20 TFs with most accessible and least accessible binding sites in plasma cell-free DNA (see Fig. 4E, Table S12 and Table S13) in localized prostate adenocarcinoma tumors from TCGA (n = 496) versus blood samples from GTEX (n = 337) (Methods). p value was calculated by Student’s t test. GTEX, Genotype-Tissue Expression project; TCGA, The Cancer Atlas Genome Atlas project; TF, transcription factor.

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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Skandalaris Center for Interdisciplinary Innovation and Entrepreneurship

V Foundation for Cancer Research (VFCR)

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ARTICLE ABSTRACT

Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSI) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood. We applied targeted cell-free DNA (cfDNA) sequencing to 126 patients with mCRPC from three academic cancer centers and separately performed genome-wide cfDNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 patients with mCRPC, respectively, to develop and validate a stem-like signature, which we inferred from cfDNA. Targeted cfDNA sequencing detected AR/enhancer alterations prior to first-line ARSIs that correlated with significantly worse progression-free survival (P = 0.01; HR = 2.12) and overall survival (P = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (P < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cfDNA revealed enrichment for stemness-associated transcription factors in patients with lethal mCRPC. The resulting stemness signature was then validated in a completely held-out cohort of 80 patients with mCRPC profiled by tumor RNA sequencing. We analyzed a total of 220 patients with mCRPC, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.See related commentary by Nawfal et al., p. 7

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Keywords

Biomarkers Circulating tumor cells/DNA/exosomes Prognostic biomarkers Epigenetics Epigenomics Genitourinary Cancers Prostate cancer Liquid Biopsy Precision Medicine Translational Research

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