ctDNA Selector Panel for Sensitive Multi-Mutation Cancer Detection
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Solution Overview
Problem
Existing methods for detecting and monitoring tumor-related nucleic acids in cancer patients are limited by the need for patient-specific optimization, sensitivity to a small number of mutations, and inability to detect genomic fusions, making them costly and less applicable for widespread clinical use.
Innovation Solution
The CAPP-Seq method combines optimized library preparation with a multi-phase bioinformatics approach to design a selector set of DNA oligonucleotides targeting recurrently mutated regions in specific cancers, enriching and sequencing circulating tumor DNA (ctDNA) to identify somatic mutations, and using software components for data analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If patient-specific optimization methods are used for detecting tumor-related nucleic acids, then detection sensitivity is improved, but manufacturing complexity and cost increase
Solution Approach 1:
The patent applies universality by developing a pan-cancer panel that can detect multiple tumor types and mutation types across different cancers using a single standardized assay platform. The panel includes probes for various mutation types (SNVs, indels, copy number variations, translocations) that work universally across different cancer types, eliminating the need for patient-specific optimization while maintaining high detection sensitivity through comprehensive coverage of recurrently mutated regions.
2Device complexity
If methods targeting a limited number of mutations are used, then assay simplicity is maintained, but detection capability is reduced
Solution Approach 1:
The patent applies segmentation by dividing the detection task into multiple independent probe targets within a single panel. Each probe targets a specific mutation type or genomic region, and the panel collectively covers numerous mutation types across different genes. This segmentation allows the assay to maintain simplicity through modular probe design while achieving comprehensive detection capability by combining results from all probe targets.
Solution Approach 2:
The patent transitions from detecting a single mutation type to detecting multiple dimensions of genomic alterations simultaneously. The panel incorporates probes for different mutation types (single nucleotide variants, insertions, deletions, copy number variations, translocations) and different genomic regions, adding dimensional complexity to the detection capability while maintaining assay simplicity through unified processing.
3Device complexity
If genomic fusions are not detected, then assay development is simplified, but diagnostic accuracy is reduced
Solution Approach 1:
The patent applies preliminary action by pre-designing probes for known fusion breakpoints and genomic regions based on existing cancer genomic data. The panel includes probes that can detect fusion events before they are identified in individual patients, allowing the assay to be ready to detect these complex alterations without requiring real-time optimization. This preliminary preparation enables fusion detection while maintaining assay development simplicity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
CAPP-Seq enables highly sensitive detection and monitoring of tumor-specific somatic mutations, allowing for cancer diagnosis, prognosis, and therapy selection with high sensitivity and specificity, even in low-abundance ctDNA.
Implementation Method 1
The methods combine optimized library preparation methods with a multi-phase bioinformatics approach to design a selector population of DNA oligonucleotides, which correspond to recurrently mutated regions in the cancer of interest
Data Source
AI summary
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.