Targeted Methylation Probe Panel for Low-Noise cfDNA Cancer Detection
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Solution Overview
Problem
Current DNA methylation profiling methods, such as whole genome bisulfite sequencing (WGBS), are not suitable for robust cancer detection due to low differentially methylated regions and high background noise, making accurate and cost-effective disease diagnosis challenging, especially when control groups are small or methylation status varies among subjects.
Innovation Solution
A targeted methylation probe panel is developed to enrich cfDNA molecules by hybridizing to specific genomic regions with anomalous methylation patterns, using overlapping probes to increase sequencing depth and reduce non-targeted nucleic acid pull-down, allowing for cancer detection and staging.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If whole genome bisulfite sequencing (WGBS) is used for DNA methylation profiling, then comprehensive methylation coverage is achieved, but cost and complexity increase significantly while diagnostic accuracy remains limited due to low differentially methylated regions
Solution Approach 1:
The patent extracts and focuses sequencing efforts only on specific genomic regions known to exhibit differential methylation in cancer, rather than sequencing the entire genome. This targeted approach isolates the diagnostically relevant information from the vast majority of the genome that provides little diagnostic value, thereby improving diagnostic accuracy while reducing sequencing complexity and cost.
Solution Approach 2:
The patent applies local quality by concentrating sequencing depth and resources on specific genomic loci that have been identified as having cancer-relevant methylation patterns. Rather than uniform genome-wide sequencing, the method enhances coverage quality at targeted regions where methylation changes are most informative for cancer detection and classification.
2Measurement precision
If whole genome sequencing is performed to ensure comprehensive coverage, then all potential methylation markers are captured, but sequencing depth at individual regions is reduced and costs increase
Solution Approach 1:
The patent extracts only the essential genomic regions relevant to cancer detection from the entire genome, concentrating sequencing resources on these targeted loci. This extraction approach achieves high sequencing depth at diagnostically important regions without the need to sequence the entire genome, thereby optimizing the balance between depth and total sequencing volume.
Solution Approach 2:
The patent applies partial action by sequencing only a subset of genomic regions that are most relevant to cancer detection, rather than performing exhaustive whole genome sequencing. This partial approach provides sufficient diagnostic information with reduced total sequencing volume while maintaining or improving depth at the targeted cancer-relevant loci.
3Productivity
If a small control group is used for identifying differentially methylated regions, then study cost and time are reduced, but the determination of differentially methylated regions loses confidence
Solution Approach 1:
The patent applies preliminary action by pre-identifying and selecting genomic regions that are known or suspected to exhibit differential methylation in cancer based on prior research and literature. This preliminary selection of targeted regions allows the method to achieve reliable cancer detection with smaller control groups, as the focus is on regions with established cancer-relevant methylation patterns rather than requiring large-scale discovery studies.
4Productivity
If targeted genomic region panels are used instead of whole genome sequencing, then sequencing depth of target regions increases and costs decrease, but coverage of potential cancer markers is reduced
Solution Approach 1:
The patent extracts and focuses on the most diagnostically relevant genomic regions for cancer detection, creating a targeted panel that prioritizes cost-effectiveness. By selecting regions with the highest likelihood of containing cancer-relevant methylation markers, the method achieves optimal diagnostic performance at reduced cost without requiring comprehensive whole genome coverage.
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
The panel provides a cost-effective, non-invasive method for early cancer detection and classification by enriching cfDNA molecules, enhancing sequencing depth and reducing background noise, thereby improving diagnostic accuracy.
Implementation Method 1
The assay panel comprises at least 500 different pairs of polynucleotide probes, wherein each pair of the at least 500 pairs of probes comprises two different probes configured to overlap with each other by an overlapping sequence of 30 or more nucleotides and is configured to hybridize to a modified fragment obtained from processing of the cfDNA molecules
Data Source
AI summary
The present description provides a cancer assay panel for targeted detection of cancer-specific methylation patterns. Further provided herein includes methods of designing, making, and using the cancer assay panel for diagnosis of cancer.