Identification and use of circulating nucleic acid tumor markers
Inventors
Diehn, Maximilian • Alizadeh, Arash Ash • Newman, Aaron M. • Bratman, Scott V.
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Assignees
Leland Stanford Junior University
MemberStanford UniversityStanford UniversityTodd Coleman is an associate professor of bioengineering at Stanford University. His research combines applied probability, physiology, and bioelectronics to develop methods and devices for monitoring and modulating nervous-system and other physiological activity, including brain and visceral-organ signals.
Todd Coleman is an associate professor of bioengineering at Stanford University. His research combines applied probability, physiology, and bioelectronics to develop methods and devices for monitoring and modulating nervous-system and other physiological activity, including brain and visceral-organ signals.
Publication Number
US-12735750-B2
Publication Date
2026-09-15
Expiration Date
Abstract
Methods for creating a selector of mutated genomic regions and for using the selector set to analyze genetic alterations in a cell-free nucleic acid sample are provided. The methods can be used to measure tumor-derived nucleic acids in a blood sample from a subject and thus to monitor the progression of disease in the subject. The methods can also be used for cancer screening, cancer diagnosis, cancer prognosis, and cancer therapy designation.
Core Innovation
The method detects cancer-associated somatic mutations in cell-free DNA from a subject with lung cancer by detecting and quantifying circulating tumor DNA. It uses an oligonucleotide selector set targeting recurrently mutated genomic regions associated with tumor-specific somatic mutations identified by comparing tumor and non-tumor sequencing information. Hybrid capture, sequencing, and bioinformatic analysis of the enriched sample detect and quantify the circulating tumor DNA.
[procedural detail omitted for safety] provides the conceptual basis for enriching targeted cell-free DNA and analyzing sequence information to detect circulating tumor DNA in a subject. In non-small cell lung cancer studies, the approximately 125-kb selector covers 96% of lung adenocarcinoma or squamous-cell tumors. The method is capable of detecting circulating tumor DNA at a proportion of no more than 2% of total cell-free DNA.
Claims Coverage
The claims identify one independent claim encompassing three inventive features directed to detecting lung-cancer circulating tumor DNA in cell-free DNA.
Selector set for tumor-specific genomic regions
The claim specifies an oligonucleotide selector set corresponding to genomic regions containing tumor-specific somatic mutations, such as at least 50 somatic mutations, identified by comparing sequencing information from tumor and non-tumor samples from a population of subjects with lung cancer.
Targeted hybrid capture and sequencing
[procedural detail omitted for safety] The claim covers enriching cell-free DNA corresponding to the selected genomic regions through hybrid capture and sequencing the captured material to generate analysis data for detecting circulating tumor DNA.
Detection at low circulating tumor DNA proportion
The claimed method is capable of detecting circulating tumor DNA at a proportion of no more than 2% of total cell-free DNA.
The independent claim integrates targeted selection of tumor-associated genomic regions with hybrid capture, sequencing, and sequence analysis of cell-free DNA to detect lung-cancer circulating tumor DNA at low proportions.
Stated Advantages
The method is capable of detecting circulating tumor DNA at a proportion of no more than 2% of total cell-free DNA to support sensitive cancer detection and monitoring.
Indel/fusion correction improves ROC performance over no correction, with a reported AUC of 0.89 versus 0.85 across all stages and 0.91 versus 0.87 for stages II–IV.
Patient-specific reporters achieve reported sensitivity and specificity of 67% and 98% for pre- and post-treatment samples across all stages, and 89% and 98% for pretreatment stages II–IV.
Targeted capture of 0.125 Mb covering four mutations provides lower cost than exome and genome sequencing while maintaining detection sensitivity.
Bead processing increases normalized yield in comparative evaluations.
The summary states a stage-IV cancer detection target of at least 60% sensitivity with greater than 90% specificity.
The approximately 125-kb selector covers 96% of lung adenocarcinoma or squamous-cell tumors.
The approach detects mutant alleles at 0.025%, with a reported detection limit below 0.01%.
Circulating tumor DNA levels correlate with tumor volume and treatment response.
Documented Applications
Generating a screening result, diagnosis, prognosis, and monitoring of lung cancer using selector-based capture and sequencing of circulating tumor DNA in cell-free DNA.
Serial plasma circulating tumor DNA measurements for longitudinal assessment, genotyping, and tracking of tumor burden and treatment response in non-small cell lung cancer patients.
Post-treatment analysis and comparison of circulating tumor DNA quantities across cell-free DNA samples to inform therapy selection and recommendations to terminate treatment, or adjust dosage or frequency.
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