Systems and methods for analyzing circulating tumor DNA
First Claim
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1. A method for analyzing tumor DNA, the method comprising:
- obtaining a genomic reference graph that represents a plurality of known human genomic sequences, the genomic reference graph comprising a directed graph having vertices and edges stored as objects in a tangible memory subsystem of a computer system, wherein matching homologous portions of the sequences are each represented by a single object and portions that vary are represented as alternate objects, such that each of the plurality of known human genomic sequences is represented as a path in the genomic reference graph;
creating a patient-specific genomic reference graph from the genomic reference graph, the creating comprising;
aligning a first set of sequencing reads, obtained by sequencing a sample containing non-tumor DNA from the patient, to the genomic reference graph;
identifying mutations relative to the genomic reference graph; and
incorporating the identified mutations as alternate objects into the genomic reference graph to create the patient-specific genomic reference graph;
aligning a second set of sequence reads, obtained by sequencing a sample containing cell-free plasma DNA from the patient, to the patient-specific genomic reference graph to find at least one mutation in the cell-free plasma DNA relative to the non-tumor DNA from the patient; and
providing a report that circulating-tumor DNA (ctDNA) in the patient includes the at least one mutation found in the cell-free plasma DNA.
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Abstract
The invention provides oncogenomic methods for detecting tumors by identifying circulating tumor DNA. A patient-specific reference directed acyclic graph (DAG) represents known human genomic sequences and non-tumor DNA from the patient as well as known tumor-associated mutations. Sequence reads from cell-free plasma DNA from the patient are mapped to the patient-specific genomic reference graph. Any of the known tumor-associated mutations found in the reads and any de novo mutations found in the reads are reported as the patient'"'"'s tumor mutation burden.
125 Citations
20 Claims
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1. A method for analyzing tumor DNA, the method comprising:
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obtaining a genomic reference graph that represents a plurality of known human genomic sequences, the genomic reference graph comprising a directed graph having vertices and edges stored as objects in a tangible memory subsystem of a computer system, wherein matching homologous portions of the sequences are each represented by a single object and portions that vary are represented as alternate objects, such that each of the plurality of known human genomic sequences is represented as a path in the genomic reference graph; creating a patient-specific genomic reference graph from the genomic reference graph, the creating comprising;
aligning a first set of sequencing reads, obtained by sequencing a sample containing non-tumor DNA from the patient, to the genomic reference graph;
identifying mutations relative to the genomic reference graph; and
incorporating the identified mutations as alternate objects into the genomic reference graph to create the patient-specific genomic reference graph;aligning a second set of sequence reads, obtained by sequencing a sample containing cell-free plasma DNA from the patient, to the patient-specific genomic reference graph to find at least one mutation in the cell-free plasma DNA relative to the non-tumor DNA from the patient; and providing a report that circulating-tumor DNA (ctDNA) in the patient includes the at least one mutation found in the cell-free plasma DNA. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
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11. A system for analyzing tumor DNA, the system comprising a processor coupled to a memory subsystem having stored therein:
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a genomic reference graph representing a plurality of known human genomic sequences, the genomic reference graph comprising a directed graph having vertices and edges stored as objects, wherein matching homologous portions of the sequences are each represented by a single object and portions that vary are represented as alternate objects, such that each of the plurality of known human genomic sequences is represented as a path in the genomic reference graph, the objects stored in the memory subsystem; and instructions executable by the processor to cause the system to; create a patient-specific genomic reference graph from the genomic reference graph, the creating comprising;
aligning a first set of sequence reads, obtained by sequencing a sample containing non-tumor DNA from the patient, to the genomic reference graph;
identifying mutations relative to the genomic reference graph; and
incorporating the identified mutations as alternate objects into the genomic reference graph to create the patient-specific genomic reference graph;align a second set of sequence reads from cell-free plasma DNA of the patient to the patient-specific genomic reference graph to find at least one mutation in the cell-free plasma DNA relative to the non-tumor DNA from the patient; and provide a report that circulating-tumor DNA (ctDNA) in the patient includes the at least one mutation found in the cell-free plasma DNA. - View Dependent Claims (12, 13, 14, 15, 16, 17, 18, 19, 20)
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Specification