Methods for using mosaicism in nucleic acids sampled distal to their origin

Inventors

West, John

Assignees

Personalis Inc

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 methods for monitoring, diagnosing or detecting disease in a human cancer patient by detecting genetic variations through patient-specific mosaic variants. A first assay on nucleic acid molecules extracted from a first sample is performed using whole genome sequencing, and mosaic variants specific to the human cancer patient are determined by alignment of sequence reads generated using whole genome sequencing to a normal reference genome of the human cancer patient. The presence or absence of the mosaic variants is then identified by performing a second assay on nucleic acid molecules extracted from one or more additional samples.

The invention further uses mutation maps to localize distal genetic signals to tissue sources. Mutation maps relate differential genetic variants to tissue sources using spatial and/or developmental trees, including a developmental mutation map and a spatial mutation map, and are computed from sequencing of nucleic acids from multiple tissues. Differential mutations, including mosaic variants, detected in distal nucleic acids are compared to the mutation map to identify mutation and tissue source relationships for disease monitoring.

In addition, the invention includes embodiments that support repeated and patient-specific monitoring and reporting. Distal nucleic acids from distal blood-associated fractions are assayed for the presence or absence of mosaic variants, including subsets known to be associated with cancer, and reports are generated based on those results. The described applications include monitoring tissue health and identifying tissue of tumor metastasis origin, with at least an example involving pancreatic cancer localization and tumor metastasis origin mapping.

Claims Coverage

The relevant independent claims are directed to monitoring, diagnosing or detecting disease in a human cancer patient using patient-specific mosaic variants across assays, monitoring, diagnosing or detecting disease using a cancer-associated subset of mosaic variants, and identifying mosaic variants specific to a subject in a blood sample using plasma cell-free nucleic acids and reporting. The inventive features across these independent claims include whole genome sequencing aligned to a normal reference genome to determine patient-specific mosaic variants, deep sequencing of those mosaic variants in additional samples, and providing reports based on presence or absence, with further constraints on cancer-associated subsets and specified genomic regions.

Across the independent claims, the core coverage is the generation of patient-specific mosaic variants via whole genome sequencing aligned to a normal reference genome, followed by deep sequencing-based detection of those mosaic variants in additional samples and reporting based on presence or absence. Further independent-claim distinctions include assaying a cancer-associated subset of mosaic variants and, in the blood/plasma embodiment, defining a subset of genomic regions (HLA genes and/or hypervariable regions) for plasma cell-free nucleic acid detection with report.

Stated Advantages

Documented Applications