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 describes analyzing biological samples obtained from a subject to improve detection and monitoring of a disease or cancer using genetic mosaicism detected in nucleic acids from non-fetal sources. Whole genome sequencing is used to generate first and second sets of sequence reads from nucleic acid molecules derived from a first set of nucleic acid molecules and a second set of nucleic acid molecules. The approach identifies mosaic variants specific to a tissue sample or to a subject in one sample that are not present in another sample from the same subject.

The method further links identified mosaic variants to prediction, diagnosis, and/or prognosis of a status or outcome of a cancer or disease or condition in the subject. After identifying mosaic variants specific to a tissue sample or to the subject in a first sample, the method identifies the mosaic variants in an additional sample obtained from a different source and/or at a different time point, and then provides a report based on that identification. The additional sample is used to support longitudinal or cross-source assessment of the status or outcome.

For blood-based approaches, the invention separates components of a blood sample to extract nucleic acid molecules from a first component and nucleic acid molecules from leukocytes in a second component. The method quantitating the nucleic acids in the first component against a reference quantity determines whether whole genome sequencing is performed. Mosaic variants are then identified by comparing sequence reads from the first and second sets, followed by identification in a later sample and reporting for early disease detection.

Claims Coverage

The partial content provides two independent claims that cover (i) analyzing a non-fetal biological sample from a cancer-screened subject using subject-specific mosaic variants identified by comparing tissue-derived nucleic acids and leukocytes, and (ii) early disease detection using blood-derived separated nucleic-acid components, optional sequencing based on quantitation against a reference, and subsequent identification of mosaic variants in a later sample. Across the two independent claims, the core inventive features repeatedly emphasize sample-source separation (tissue or blood components vs leukocytes), identification of mosaic variants absent from the comparison sample, subsequent detection in a different source/time point sample, and reporting to predict, diagnose, and/or prognose an outcome.

The independent claims cover identification of subject-specific mosaic variants by comparing sequence reads from a primary sample source (tissue or a blood component) versus leukocytes, followed by re-identification of the mosaic variants in a later sample from a different source/time point and reporting to predict, diagnose, and/or prognose a cancer status or disease outcome.

Stated Advantages

Documented Applications