Urine cfDNA Size Profiling for Bladder Cancer Detection
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Solution Overview
Problem
Current methods for analyzing cell-free DNA in urine are limited by high variability in the proportional contribution of different tissue sources, making it difficult to detect cancer or other diseases using non-invasive biopsies like urine samples, as the concentration of cfDNA from specific sources is often low or undetectable, and existing techniques require prior identification of specific point mutations.
Innovation Solution
The use of methylation deconvolution and size profiling of cell-free DNA fragments in urine samples to determine the proportional contribution of different tissue types, including diseased tissues, allowing for the identification of cancerous conditions by analyzing tissue-specific methylation patterns and fragment sizes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If urine samples are used for non-invasive cancer detection, then the invasiveness of the procedure is reduced, but the detection reliability deteriorates due to low concentration and high variability of cfDNA from specific tissue sources
Solution Approach 1:
The patent transforms the detection approach by changing from measuring absolute cfDNA concentration to analyzing the size distribution parameters of cfDNA fragments. By focusing on the size profile (length distribution) rather than concentration, the method overcomes the variability problem while maintaining non-invasive sampling advantages
Solution Approach 2:
The patent develops a universal detection method that can identify multiple tissue sources (bladder, kidney, prostate, etc.) using a single urine sample analysis. The size profiling approach works across different cancer types and tissue origins without requiring source-specific assays, making the technique broadly applicable
2Measurement precision
If point mutation analysis is used for cancer monitoring, then the detection specificity is improved, but the applicability to screening asymptomatic patients deteriorates because specific mutations must be identified beforehand
Solution Approach 1:
Instead of starting with known mutations and searching for them (traditional approach), the patent inverts the logic by analyzing the size characteristics of cfDNA and inferring tissue origin and cancer presence without prior knowledge of specific genetic alterations. This enables screening of asymptomatic patients where no target mutations are predetermined
Solution Approach 2:
The patent changes the detection parameter from genetic sequence (point mutations) to physical characteristic (fragment size). This parameter shift allows detection of any cancer type regardless of specific mutations, enabling broad screening while maintaining detection precision through size-profile analysis
3Measurement precision
If cfDNA concentration from a single tissue source is measured, then the detection sensitivity for that specific source is improved, but the ability to detect multiple tissue sources simultaneously deteriorates
Solution Approach 1:
The patent segments the total cfDNA population into size-based categories and analyzes the distribution across multiple size ranges. This segmentation allows simultaneous detection of different tissue sources, each contributing characteristic size profiles to the overall distribution, enabling multi-source detection while maintaining sensitivity for individual sources
Data Source
AI summary
Diseases (e.g., cancer) of a particular organ can be detected by analyzing cell-free DNA. Some embodiments may use an organ-associated sample that is from a particular organ or passes through the particular organ, as may occur, for example, in urine, saliva, blood, and stool samples. In some embodiments, methylation levels of cell-free DNA can be measured in a sample. Tissue-specific methylation patterns can be used to determine fractional contributions from different tissue types. In other embodiments, sizes of organ-associated cell-free DNA can be measured. A statistical measure of the size profile may indicate that cell-free DNA fragments are collectively longer than expected for subjects with healthy tissue compared to non-healthy tissue. In other embodiments, two different samples can be analyzed to determine whether a particular organ has cancer. Cell-free DNA in a blood sample and organ-associated sample can both be analyzed to identify chromosomal regions exhibiting a copy number aberration.