Cell-Free DNA Mutation Detection for Non-Invasive Cancer Screening
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Solution Overview
Problem
Current cancer screening methods based on direct analysis of predetermined mutations in cell-free plasma/serum have low accuracy and require invasive surgical biopsies for genetic information, increasing risks and costs.
Innovation Solution
A method for identifying somatic mutations in plasma using random sequencing and filtering techniques, such as dynamic cutoffs, realignment, and mutation fraction analysis, to detect cancer-specific mutations without prior knowledge of tumor genetics, enabling non-invasive cancer screening and monitoring.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If direct analysis of predetermined mutations is used for cancer screening, then the screening process is simplified, but the accuracy of cancer detection decreases
Solution Approach 1:
The patent extracts and analyzes individual somatic mutations from cell-free plasma DNA without requiring prior knowledge of specific mutation panels. Instead of analyzing predetermined mutations, the method randomly sequences plasma DNA fragments and identifies somatic mutations de novo, thereby maintaining operational simplicity while significantly improving detection accuracy across diverse cancer types.
Solution Approach 2:
The patent changes the fundamental parameter of mutation analysis from targeted predetermined mutations to random somatic mutation detection. By altering the approach from analyzing known cancer-associated mutations to detecting any somatic mutation present in plasma DNA, the method achieves broader cancer detection capability with maintained ease of operation.
2Loss of information
If surgical biopsies are performed to obtain tumor genetic information, then comprehensive genetic data is obtained, but patient risk and costs increase
Solution Approach 1:
The patent uses cell-free plasma DNA as an intermediary to obtain tumor genetic information without direct tumor tissue sampling. The plasma DNA serves as a liquid biopsy surrogate, containing somatic mutations from the tumor that can be analyzed to obtain comprehensive genetic data while avoiding the risks and costs associated with surgical biopsies and expensive imaging scans.
Solution Approach 2:
The patent replaces the mechanical invasive procedure of surgical biopsy with a non-invasive blood draw and molecular sequencing approach. By substituting the physical tissue removal and analysis mechanism with plasma DNA extraction and next-generation sequencing, the method maintains genetic information completeness while eliminating surgical risks and reducing overall costs.
3Difficulty of detecting and measuring
If expensive scanning techniques are used to locate tumors before biopsy, then accurate tumor localization is achieved, but costs increase
Solution Approach 1:
The patent extracts tumor genetic information directly from circulating plasma DNA without requiring prior tumor localization through expensive imaging scans. By taking out the need for anatomical imaging and directly analyzing the molecular signature of tumor DNA in the blood, the method achieves accurate cancer detection while eliminating the cost of scanning techniques.
4Loss of information
If a panel of predetermined mutations is analyzed, then the analysis scope is limited to known mutations, but the view of tumor genetics becomes restricted
Solution Approach 1:
The patent creates a universal mutation detection method that can identify any somatic mutation in plasma DNA regardless of whether it is predetermined or newly discovered. The approach simultaneously detects known cancer-associated mutations and novel somatic mutations, providing comprehensive coverage of tumor genetic diversity while maintaining a single versatile analytical framework applicable to various cancer types.
Data Source
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AI summary
A method for identifying somatic mutations by analyzing a biological sample including cell-free DNA fragments from a human subject, is provided. The method comprises receiving one or more sequence reads for each of a plurality of DNA fragments in the biological sample, and comparing the sequence reads to a constitutional genome to identify sequence variants. For each of a first set of candidate loci identified as having a sequence variant, a size difference is determined between a first group of DNA fragments having the sequence variant and a second group of DNA fragments having a wildtype allele. The size difference is compared to a size threshold and the candidate locus is discarded based on whether the size difference is less than the size threshold. One or more somatic mutations are identified using the remaining candidate loci.