Transcription factor–nucleosome dynamics from plasma cfDNA identifies ER-driven states in breast cancer

Rao, Satyanarayan; Han, Amy; Zukowski, Alexis; Kopin, Etana; Sartorius, Carol A.; Kabos, Peter; Ramachandran, Srinivas

doi:10.1126/sciadv.abm4358

Cited by 13 publications

(8 citation statements)

References 69 publications

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“…Overall, they discovered that the intensity of TF footprints in plasma was proportional to the intensity of TF binding in the tissue of origin of cfDNA fragments. This study demonstrated that plasma cfDNA contains tumour‐specific TF binding information, which can be used to investigate tumour‐specific regulation 62 …”

Section: Transcription Factor Binding Sitesmentioning

confidence: 83%

“…This study demonstrated that plasma cfDNA contains tumourspecific TF binding information, which can be used to investigate tumour-specific regulation. 62 Moreover, with the increasing attention to cfDNA features, researchers are contemplating how to enhance the accuracy of the correlation between cfDNA fragment coverage and gene expression. In 2023, Doebley et al developed Griffin, a framework for analysing nucleosome protection and cfDNA accessibility.…”

Section: Transcription Factor Binding Sitesmentioning

confidence: 99%

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Cell‐free DNA‐associated multi‐feature applications in cancer diagnosis and treatment

Zhang,

Li,

Lan

et al. 2024

Clinical and Translational Dis

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Malignant tumours pose significant challenges in terms of high morbidity and mortality rates, primarily due to the lack of large‐scale applicable screening methods and efficient treatment strategies. However, the development of liquid biopsies, particularly circulating cell‐free DNA (cfDNA), offers promising solutions characterised by their non‐invasiveness and cost‐effectiveness, providing comprehensive tumour information on a global scale. The release of cfDNA is predominantly associated with cell death and turnover, while its elimination occurs through nuclease digestion, renal excretion into the urine and uptake by the liver and spleen. Extensive research into the biological properties of cfDNA has led to the identification of novel applications, including non‐invasive cancer screening, cancer subtype classification, tissue‐of‐origin detection and monitoring of treatment efficacy. Additionally, emerging fields such as methylation‐omics, fragment‐omics and nucleosome‐omics show immense potential as tissue‐ and disease‐specific markers. Therefore, this review aims to comprehensively introduce the latest detection techniques of cfDNA, along with detailed information on its characteristics and applications, providing valuable insights for cancer diagnosis and monitoring, which will assist us in purposefully enhancing relevant features for a more comprehensive application in clinical practice.

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Section: Transcription Factor Binding Sitesmentioning

confidence: 83%

Section: Transcription Factor Binding Sitesmentioning

confidence: 99%

Cell‐free DNA‐associated multi‐feature applications in cancer diagnosis and treatment

Zhang,

Li,

Lan

et al. 2024

Clinical and Translational Dis

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“…Because of the scarcity of POU2F3-expressing PDX models, our "PDX" set included one POU2F3 PDX (never passaged ex vivo) and three POU2F3-expressing SCLC cell line xenograft models. In PDX plasma samples, tumor and nontumor cfDNA are from different species and can be separated bioinformatically to generate a pure tumor (human) cfDNA signal (37,39). We excluded low-coverage samples, resulting in an analysis set of 19 SCLC and 6 NSCLC PDX models (see Materials and Methods, Fig.…”

Section: Cfdna Sequencing For Integrated Mutation Detection and Infer...mentioning

confidence: 99%

Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions

Hiatt,

Doebley,

Arnold

et al. 2024

Sci. Adv.

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We report an approach for cancer phenotyping based on targeted sequencing of cell-free DNA (cfDNA) for small cell lung cancer (SCLC). In SCLC, differential activation of transcription factors (TFs), such as ASCL1, NEUROD1, POU2F3, and REST defines molecular subtypes. We designed a targeted capture panel that identifies chromatin organization signatures at 1535 TF binding sites and 13,240 gene transcription start sites and detects exonic mutations in 842 genes. Sequencing of cfDNA from SCLC patient-derived xenograft models captured TF activity and gene expression and revealed individual highly informative loci. Prediction models of ASCL1 and NEUROD1 activity using informative loci achieved areas under the receiver operating characteristic curve (AUCs) from 0.84 to 0.88 in patients with SCLC. As non-SCLC (NSCLC) often transforms to SCLC following targeted therapy, we applied our framework to distinguish NSCLC from SCLC and achieved an AUC of 0.99. Our approach shows promising utility for SCLC subtyping and transformation monitoring, with potential applicability to diverse tumor types.

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“…Such DNA fragments are protected from nuclease digestion by nucleosomes and other DNA-bound proteins, and therefore cfDNA analysis allows to reconstruct nucleosome maps. This natural process is similar to MNase-seq experiments where chromatin is digested between nucleosomes by micrococcal nuclease (MNase), and MNase-resistant DNA fragments are analysed (6)(7)(8)(9)(10)(11)(12). Nucleosome positioning is also related to chromatin accessibility profiled with experiments such as ATAC-seq (13), although the latter is focused on open chromatin regions and does not provide high-resolution nucleosome maps like MNase-seq.…”

Section: Introductionmentioning

confidence: 99%

Nucleosome reorganisation in breast cancer tissues

Jacob

Guiblet

Mamayusupova

et al. 2023

Preprint

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Nucleosome repositioning in cancer highlights changes of many aspects of genome organisation and regulation. Understanding it is important both from the fundamental point of view and for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. Here we generated ultra-high resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma. We detected cancer-specific single-nucleosome repositioning at key regulatory regions in a patient-specific manner, as well as common patterns across patients. The nucleosomes gained in tumour versus normal tissue were particularly informative of cancer pathways, with 20-fold enrichment at CpG islands, a large fraction of which marked promoters of genes encoding DNA-binding proteins. Tumour tissues were characterised by 5-10 bp decrease in average distances between nucleosomes (nucleosome repeat length, NRL). These effects were modulated by GC content and DNA sequence repeats and correlated with differential DNA methylation and binding of linker histone variants H1.4 and H1X. Our findings provide missing mechanistic understanding of nucleosome positioning in tumour tissues and can be valuable for nucleosomics analyses in liquid biopsies.

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Transcription factor–nucleosome dynamics from plasma cfDNA identifies ER-driven states in breast cancer

Cited by 13 publications

References 69 publications

Cell‐free DNA‐associated multi‐feature applications in cancer diagnosis and treatment

Cell‐free DNA‐associated multi‐feature applications in cancer diagnosis and treatment

Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions

Nucleosome reorganisation in breast cancer tissues

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