Methods for using mosaicism in nucleic acids sampled distal to their origin
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Publication Number
US-11965214-B2
Publication Date
2024-04-23
Expiration Date
Abstract
Disclosed herein are methods for improving detection and monitoring of human diseases. The methods can be used to provide spatial and/or developmental localization of the source of each differential mutation within the body. The methods can also be used to generate a mutation map of a subject. And the mutation map can be used to monitoring state(s) of health of one or more tissues of a subject.
Core Innovation
The invention provides a method for detecting a presence or recurrence of a cancer by using nucleic-acid mosaicism and creating subject-specific mutation maps that link differential mutations to tissue origin. Nucleic-acid molecules are obtained from at least a first tissue sample and a second tissue sample from a subject, where the first tissue sample is obtained from a source different than the second tissue sample and includes benign tissue, malignant tissue, or mixed tissue, while the second tissue sample includes a normal sample. The method includes extracting nucleic acid molecules from both tissue samples and independently sequencing the extracted nucleic acid molecules to generate sequence reads from each sample.
Mosaic variants are identified by comparing the first set of sequence reads with the second set of sequence reads using a programmed computer processor. The mosaic variants are identified in sequence reads present in the first set that are not present in the second set. Based on the identification of the mosaic variants, a first report is created. In the described approaches, the mutation map can be a developmental mutation map and/or a spatial mutation map, constructed from differential mutations detected across multiple tissues using sequencing to support mapping of tissue origin.
After the tissue-based identification, one or more blood samples are obtained at a later time point than the first tissue sample and the second tissue sample. Nucleic acid molecules are extracted from the blood samples and a sequencing assay is performed to identify the presence or absence of the mosaic variants one or more times over the life of the subject. A second report is provided based on the presence or absence of the mosaic variants in the blood samples, thereby detecting the presence or recurrence of the cancer in the subject. The disclosed implementations include identifying tissue of origin for tumor metastases using a mutation map and monitoring tissue health states by mapping detected mutations back to a mutation map.
Claims Coverage
The provided independent claim is clm-00001. It covers 2 inventive features: tissue-based independent sequencing to identify mosaic variants, and longitudinal blood sequencing of identified mosaic variants to detect cancer presence or recurrence.
Tissue-based independent sequencing to identify mosaic variants
Obtaining at least a first tissue sample and a second tissue sample, extracting nucleic acid molecules from the first and second tissue samples, independently sequencing the extracted nucleic acid molecules to generate first and second sets of sequence reads, and comparing the first and second sets with a programmed computer processor to identify mosaic variants present in the first set but not in the second set.
Longitudinal blood sequencing of identified mosaic variants
Creating a first report based on identification of the mosaic variants; obtaining one or more blood samples at a later time point than the first and second tissue samples; extracting nucleic acid molecules from the blood samples; performing a sequencing assay on the extracted nucleic acid molecules to identify the presence or absence of the mosaic variants one or more times over the life of the subject; and providing a second report based on the presence or absence of the mosaic variants in the blood samples, thereby detecting the presence or recurrence of the cancer.
Overall, the claim coverage centers on independently sequencing different tissue sources versus normal tissue to identify mosaic variants via read comparison, and then assaying those mosaic variants in later blood samples over time to provide a report that detects cancer presence or recurrence.
Stated Advantages
Detecting the presence or recurrence of the cancer in the subject using later blood sample sequencing based on mosaic variants identified from tissue comparisons.
Enabling longitudinal monitoring over the life of the subject by identifying the presence or absence of mosaic variants in one or more blood samples at later time points.
Documented Applications
Early cancer detection using distal cfDNA mosaicism mapped to tumor origin, including pancreatic cancer from distal cfDNA.
Identifying tissue of origin for tumor metastases using a mutation map constructed from detected mutations.
Monitoring tissue health states by mapping detected mutations back to a mutation map.
Detecting presence or recurrence of cancer by assaying identified mosaic variants in blood samples over time.
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