cfDNA Fragmentomic Cancer Detection via Targeted Exon Sequencing
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Solution Overview
Problem
Current methods for detecting cancer using cell-free DNA (cfDNA) face challenges with low sensitivity and specificity due to the need for whole-genome sequencing, which is unsuitable for detecting somatic alterations, especially at low ctDNA fractions, and fail to capture fragmentomic regions of interest predominantly found in non-coding regions of the genome.
Innovation Solution
A method involving the determination of fragmentation patterns of classifier cfDNA corresponding to specific exon regions of cancer genes, using targeted sequencing to identify cancer types or subtypes by classifying fragmentation patterns, allowing for high sequencing depth and specificity, and excluding non-classifier cfDNA to improve detection accuracy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Area of stationary object
If whole-genome sequencing is used for fragmentomic analysis, then genome-wide coverage is achieved, but sequencing depth is insufficient for detecting somatic alterations at low ctDNA fractions
Solution Approach 1:
The patent segments the genome into specific regions of interest (exons of cancer-related genes, non-coding regions with fragmentomic signals) and concentrates sequencing resources on these segments. This allows achieving high sequencing depth (hundreds to thousands of times coverage) for targeted regions while maintaining comprehensive cancer detection capability, resolving the contradiction between genome-wide coverage and sequencing depth.
2Measurement precision
If targeted cfDNA panels are used, then sequencing depth and sensitivity are improved, but fragmentomic regions in non-coding regions are not captured
Solution Approach 1:
The patent designs a multi-functional targeted panel that simultaneously captures coding regions (exons) and non-coding regions with fragmentomic signals. The panel includes both traditional cancer gene exons and regulatory regions such as promoters, enhancers, and transcription factor binding sites, enabling comprehensive fragmentomic analysis within a targeted sequencing framework, thus achieving both high sequencing depth and broad fragmentomic coverage.
3Reliability
If traditional coding targeted panels are used, then somatic alterations in coding regions are detected, but fragmentomic patterns in non-coding regions are missed
Solution Approach 1:
The patent merges two previously separate approaches: traditional coding-region targeted panels and non-coding region fragmentomic analysis. The integrated panel combines exons of cancer-related genes with adjacent non-coding regions including promoters, enhancers, and other regulatory elements, allowing simultaneous detection of somatic alterations and fragmentomic patterns in a unified assay, thereby preventing loss of fragmentomic information while maintaining reliable somatic alteration detection.
Data Source
AI summary
Methods of detecting cancer or a particular type or subtype thereof in a subject and treating the cancer or particular type or subtype thereof. The detection can comprise determining fragmentation patterns of classifier cell-free deoxyribonucleic acid (cfDNA) from the subject and classifying the fragmentation patterns to identify the subject as being negative or positive for the cancer or the particular type or subtype thereof. The classifier cfDNA can comprise cfDNA corresponding to at least a portion of at least one exon of one or more classifier genes. The exon can comprise the first exons of the classifier genes. The treating can comprise the specific type of subtype of cancer that is detected.