Liquid biopsy to detect cancer early and sensitively in patients with neurofibromatosis type 1
Inventors
Chaudhuri, Aadel • Jones, Paul • Szymanski, Jeffrey • Hirbe, Angela • Sundby, Russell • Shern, John
Assignees
Washington University in St Louis WUSTL • National Institutes of Health NIH
Publication Number
US-12140595-B2
Publication Date
2024-11-12
Expiration Date
2042-01-27
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Abstract
Among the various aspects of the present disclosure is the provision of methods for detecting cancer in Neurofibromatosis Type 1 (NF1) patients.
Core Innovation
The invention provides methods and compositions for the detection of cancer, specifically malignant peripheral nerve sheath tumor (MPNST), in patients diagnosed with Neurofibromatosis Type 1 (NF1) using a liquid biopsy approach analyzing cell-free DNA (cfDNA) from plasma samples. This involves ultra-low-pass whole genome sequencing (ULP-WGS) of cfDNA to detect genomic alterations such as copy number variations and fragmentation profiles indicative of malignant transformation from benign plexiform neurofibroma (PN) to MPNST.
The problem being addressed is the difficulty in early and sensitive detection of MPNST in NF1 patients due to the inability of imaging and biopsy methods to distinguish malignant tumors from their benign precursors. Existing methods suffer from low specificity and sensitivity, sampling errors due to tumor heterogeneity, and morbidity associated with invasive biopsies. There is a pressing need for non-invasive, reliable screening tools to detect transformation from PN to MPNST early and to monitor disease burden and treatment response.
Claims Coverage
The patent includes two independent claims describing methods for selecting treatment for NF1 patients by analyzing cfDNA using ultra-low-pass whole genome sequencing.
Detection of malignant transformation through cfDNA fragment size distribution analysis
Providing a blood sample from an NF1 patient, isolating cfDNA, performing ULP-WGS to obtain reads with fragment size information, comparing the distribution of these fragment sizes within the range of about 90 bp to about 150 bp to a reference distribution from non-MPNST patients, and predicting transformation to MPNST if the sample is enriched for shorter fragments (<138 bp) and depleted for longer fragments (≥138 bp).
Detection of malignant transformation through tumor fraction estimation from copy number alterations
Aligning read sequences from cfDNA ULP-WGS to a reference genome, estimating local copy numbers, identifying copy number alterations by comparison to reference copy numbers from non-MPNST populations, calculating a tumor fraction from these alterations, and predicting NF1 to MPNST transformation if the tumor fraction exceeds a threshold (range about 0.01 to 0.05, e.g., about 0.041).
Use of ULP-WGS coverage parameters and disease burden estimation
Performing ULP-WGS at genomic coverage between about 0.3× to about 0.6× and, based on the estimated tumor fraction, further estimating disease burden in the patient.
These inventive features together define non-invasive methods employing ultra-low-pass whole genome sequencing of cfDNA to detect malignant transformation in NF1 patients by analyzing fragment size distributions and tumor fraction derived from copy number alterations, enabling informed selection of treatments such as surgical resection.
Stated Advantages
Enables early and sensitive identification of cancer in NF1 patients non-invasively without the need for biopsy.
Improves specificity and sensitivity over standard clinical and imaging exams for detecting malignant transformation from PN to MPNST.
Allows dynamic monitoring of tumor burden and treatment response through serial plasma sampling.
Overcomes geographic tumor heterogeneity issues inherent in biopsy by analyzing tumor-derived cfDNA in plasma.
Facilitates personalized and precise clinical management by enabling real-time detection and tracking of tumor genomic and epigenomic alterations.
Documented Applications
Non-invasive early detection of malignant peripheral nerve sheath tumor (MPNST) in patients with Neurofibromatosis Type 1 (NF1).
Monitoring tumor burden and response to treatment in NF1 patients diagnosed with MPNST through serial cfDNA analysis.
Guiding clinical decisions such as selection of resection treatment based on prediction of malignant transformation from cfDNA sequencing data.
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