Methods and Systems for Analyzing Nucleic Acid Molecules

Abstract

Processes and materials to detect cancer from a biopsy are described. In some cases, cell-free nucleic acids can be sequenced, and the sequencing result can be utilized to detect sequences derived from a neoplasm. Detection of somatic variants occurring in phase can indicate the presence of cancer in a diagnostic scan and a clinical intervention can be performed.

What is claimed is: 
     
         1 . A method of monitoring a progress of a condition of a subject, the method comprising:
 (a) determining a first state of the condition of the subject based on identification of a first set of one or more cell-free nucleic acid molecules from a first plurality of cell-free nucleic acid molecules that is obtained or derived from the subject;   (b) determining a second state of the condition of the subject based on identification of a second set of one or more cell-free nucleic acid molecules from a second plurality of cell-free nucleic acid molecules that is obtained or derived from the subject,
 wherein the second plurality of cell-free nucleic acid molecules are obtained from the subject subsequent to obtaining the first plurality of cell-free nucleic acid molecules from the subject; and 
   (c) determining the progress of the condition based on the first state of the condition and the second state of the condition;   wherein each of the one or more cell-free nucleic acid molecules comprises a plurality of phased variants relative to a reference genomic sequence that are separated by at least one nucleotide.   
     
     
         2 . The method of  claim 1 , wherein the progress of the condition comprises worsening of the condition. 
     
     
         3 . The method of  claim 1 , wherein the progress of the condition comprises at least a partial remission of the condition. 
     
     
         4 . The method of  claim 1 , wherein the second plurality of cell-free nucleic acid molecules is obtained from the subject at least about 1 week subsequent to obtaining the first plurality of cell-free nucleic acid molecules from the subject. 
     
     
         5 . The method of  claim 1 , wherein the subject undergoes a treatment for the condition (i) prior to obtaining the second plurality of cell-free nucleic acid molecules from the subject and (ii) subsequent to obtaining the first plurality of cell-free nucleic acid molecules from the subject. 
     
     
         6 . The method of  claim 1 , wherein the progress of the condition is indicative of minimal residual disease of the condition of the subject. 
     
     
         7 . The method of  claim 1 , wherein the progress of the condition is indicative of tumor burden or cancer burden of the subject. 
     
     
         8 . The method of  claim 7 , further comprising enriching for the one or more cell-free nucleic acid molecules from among the plurality of cell-free nucleic acid molecules. 
     
     
         9 . The method of  claim 1 , wherein the one or more cell-free nucleic acid molecules are captured from among the plurality of cell-free nucleic acid molecules with a set of nucleic acid probes, wherein the set of nucleic acid probes is configured to hybridize to at least a portion of cell-free nucleic acid molecules comprising one or more genomic regions associated with the condition. 
     
     
         10 . A method of monitoring progress of a condition, the method comprising:
 (a) obtaining, by a computer system, sequencing data for a plurality of DNA molecules obtained from a subject at a first timepoint;   (b) processing, by the computer system, the sequencing data for the plurality of DNA molecules obtained from the subject at the first timepoint to identify and determine genomic locations of a plurality of disease-derived phased-variant containing DNA molecules, wherein the identity and genomic locations of the disease-derived DNA molecules are determined based on alignment of reads corresponding to each of the plurality of DNA molecules to a reference genomic sequence;   (c) obtaining, by the computer system, sequencing data for a plurality of cell-free DNA molecules obtained from the subject at a second timepoint that is subsequent to the first timepoint; and   (d) aligning, by the computer system, the sequencing data for the plurality of cell-free DNA molecules obtained from the subject at the second timepoint to the genomic locations of the plurality of disease-derived phased-variant containing DNA identified in (b) to assess an extent to which the cell-free DNA molecules from the subject at the second timepoint comprise disease-derived phased-variant containing cell-free DNA molecules.   
     
     
         11 . The method of  claim 10 , wherein the plurality of DNA molecules obtained from the subject at the first timepoint are tumor-derived DNA molecules. 
     
     
         12 . The method of  claim 10 , wherein the plurality of DNA molecules obtained from the subject at the first timepoint are cell-free DNA molecules. 
     
     
         13 . The method of  claim 10 , wherein the sequencing data comprises whole genome sequencing data. 
     
     
         14 . The method of  claim 10 , wherein the disease is a cancer. 
     
     
         15 . The method of  claim 10 , further comprising determining a cancer burden or a tumor burden of the subject. 
     
     
         16 . The method of  claim 10 , wherein the extent to which the cell-free DNA molecules from the subject at the second timepoint comprise disease-derived phased-variant containing cell-free nucleic acid molecules is used to determine minimal residual disease. 
     
     
         17 . The method of  claim 10 , wherein the progress of the condition comprises worsening of the condition. 
     
     
         18 . The method of  claim 10 , wherein the progress of the condition comprises at least partial remission of the condition. 
     
     
         19 . The method of  claim 10 , wherein the progress of the condition comprises full remission of the condition. 
     
     
         20 . The method of  claim 10 , wherein the second timepoint is at least about 1 week subsequent to the first timepoint. 
     
     
         21 . The method of  claim 10 , wherein the subject is subjected to a treatment for the condition (i) prior to the second timepoint and (ii) subsequent to the first timepoint. 
     
     
         22 . The method of  claim 10 , further comprising enriching for cell-free DNA molecules corresponding to the genomic locations identified in (b) to obtain the plurality of cell-free DNA molecules obtained from the subject at the second timepoint. 
     
     
         23 . The method of  claim 22 , wherein the enriching for cell-free DNA molecules corresponding to the genomic locations identified in (b) comprises hybridization capture. 
     
     
         24 . The method of  claim 10 , wherein the disease-derived phased variant-containing cell-free nucleic acid molecules identified in (b) each comprise a plurality of phased variants relative to the reference genomic sequence that are separated by at least one nucleotide. 
     
     
         25 . The method of  claim 10 , wherein the plurality of DNA molecules obtained from the subject at the first timepoint comprises at least 1000 molecules.