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Publication Number
US-12682984-B2
Publication Date
2026-07-14
Expiration Date
Abstract
Methods and systems disclosed herein can improve analysis capabilities of genomic materials. The methods provided herein may examine transcription factor binding site accessibility to diagnose a disease or monitor progression of a disease in a subject.
Core Innovation
The method treats cancer in a human subject using cell-free DNA whole-genome sequencing and transcription-factor binding-site accessibility profiling. Read-depth coverage patterns comprising nucleosome data across flanking genomic regions characterize binding-site accessibility. The method separates low-frequency and high-frequency signals, normalizing high-frequency signals with low-frequency signals to determine accessibility scores. Deviations of accessibility scores from reference scores support cancer detection, followed by administering a therapeutic intervention.
The disclosure evaluates cancer conditions including breast cancer, colon cancer, prostate adenocarcinoma, and small-cell neuroendocrine prostate cancer. Read-depth patterns around binding sites identify site-centered accessibility changes, central read-depth depletion, and transcription-factor-specific oscillatory nucleosome patterns. Profiles for transcription factors such as GRHL2, FOXA1, HOXB13, AR, and NKX3-1 support tumor-of-origin identification, longitudinal monitoring, and assessment of prostate cancer subtype changes.
Claims Coverage
The claims identify one independent claim directed to cancer detection and treatment using cell-free DNA accessibility profiling, comprising four inventive features.
Analysis of cell-free DNA sequence reads
The method uses sequence reads obtained by whole-genome sequencing of cell-free DNA from a human subject and aligns them to a human reference genome to generate read-depth coverage patterns comprising nucleosome data flanking transcription-factor binding sites.
Binding-site accessibility scoring
The method processes read-depth coverage patterns to determine accessibility scores, separating low-frequency and high-frequency signals and using the low-frequency signal to normalize the high-frequency signal.
Cancer detection via accessibility-score deviation
The method detects cancer, comprising breast cancer, colon cancer, prostate adenocarcinoma, or small-cell neuroendocrine prostate cancer, based at least in part on deviation of an accessibility score from a reference accessibility score.
Therapeutic intervention upon cancer detection
Upon detecting cancer in the human subject, the method administers a therapeutic intervention, such as chemotherapy, surgery, or androgen deprivation therapy, to treat the cancer.
The independent claim combines cell-free DNA sequence alignment, nucleosome-based accessibility pattern generation and signal normalization, cancer detection based on score deviation, and subsequent therapeutic intervention.
Stated Advantages
The disclosure characterizes the transcription-factor accessibility profiling as non-invasive.
The analyses remain informative in reduced-read and pooled shallow-coverage samples.
Documented Applications
Detection and treatment of breast cancer, colon cancer, prostate adenocarcinoma, or small-cell neuroendocrine prostate cancer in a human subject by administering a therapeutic intervention following cell-free DNA accessibility scoring.
Cancer detection, tumor classification, and longitudinal disease monitoring using cell-free DNA whole-genome sequencing and transcription-factor accessibility profiles.
Tumor-of-origin identification.
Monitoring prostate cancer subtype changes, including adenocarcinoma-to-neuroendocrine transdifferentiation.
Assessing transcription-factor binding-site accessibility using cell-free DNA read-depth profiles.
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