US 2022/0064714 A1 · USING NUCLEIC ACID SIZE RANGE FOR NONINVASIVE CANCER DETECTION

Abstract

Size-band analysis is used to determine whether a chromosomal region exhibits a copy number aberration or an epigenetic alteration. Multiple size ranges may be analyzed instead of focusing on specific sizes. By using multiple size ranges instead of specific sizes, methods may analyze more sequence reads and may be able to determine whether a chromosomal region exhibits a copy number aberration even when clinically-relevant DNA may be a low fraction of the biological sample. Using multiple ranges may allow for the use of all sequence reads from a genomic region, rather than a selected subset of reads in the genomic region. The accuracy of analysis may be increased with higher sensitivity at similar or higher specificity. Analysis may include fewer sequencing reads to achieve the same accuracy, resulting in a more efficient process.

Claims46

Dependent claims

A method of determining whether a chromosomal region exhibits a copy number aberration in a biological sample from a subject, wherein the biological sample includes a mixture of cell-free DNA molecules including clinically-relevant DNA molecules and other DNA molecules, the method comprising:

for each size range of a plurality of size ranges:
measuring a first amount of cell-free DNA molecules from the biological sample corresponding to the size range, and
calculating, by a computer system, a size ratio using the first amount of cell-free DNA molecules corresponding to the size range and a second amount of DNA molecules in a second size range that includes sizes not in the size range;
obtaining a reference size pattern including a plurality of reference size ratios for the plurality of size ranges, wherein the reference size pattern is determined from a plurality of reference samples from subjects with a copy number aberration or from subjects without a copy number aberration in the chromosomal region;
comparing a plurality of the size ratios to the reference size pattern;
determining whether the chromosomal region exhibits a copy number aberration based on the comparison.

3 more elements

A method of determining a cancer classification in a biological sample from a subject, wherein the biological sample includes a mixture of cell-free DNA molecules including tumor DNA molecules and non-tumor DNA molecules, the method comprising:

for each genomic region of N genomic regions:
for each size range of M size ranges:
measuring a first amount of cell-free DNA molecules from the biological sample corresponding to the size range and corresponding to the genomic region, and
calculating, by a computer system, a size ratio using the first amount of cell-free DNA molecules corresponding to the size range and corresponding to the genomic region and a second amount of DNA molecules in a second size range that includes sizes not in the size range, thereby generating a measurement vector of N×M size ratios, wherein N is an integer greater than or equal to 1, and M is an integer greater than 1;
obtaining a reference size pattern including a reference vector of reference size ratios for the N genomic regions and the M size ranges, wherein the reference size pattern is determined from a plurality of reference samples from subjects with cancer or from subjects without cancer;
comparing the measurement vector to the reference vector;
and
determining a level of cancer based on the comparison.

5 more elements

enriching the biological sample for one or more sizes of the cell-free DNA molecules to form an enriched biological sample;
performing methylation-aware sequencing to identify methylated cell-free DNA molecules in the enriched biological sample;
for each size range of a plurality of size ranges:
measuring a first amount of the methylated cell-free DNA molecules from the enriched biological sample corresponding to the size range, and
determining, by a computer system, a methylation level using the first amount of the methylated cell-free DNA molecules corresponding to the size range and a second amount of DNA molecules in a second size range that includes sizes not in the size range;
obtaining, by the computer system, a reference size pattern including a reference methylation level for each size range of the plurality of size ranges, wherein the reference size pattern is determined from a plurality of reference samples from subjects with cancer or from subjects without cancer;
comparing, by the computer system, a plurality of the methylation levels to the reference size pattern;
and
determining a level of cancer based on the comparison.

6 more elements

Dependencies are inferred from the claim text.

Using nucleic acid size range for noninvasive cancer detection

Life of this patent

Using nucleic acid size range for noninvasive cancer detection

Life of this patent

Abstract

Claims46