Personalized Tumor Markers Using Structural Variant Breakpoints
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current computational methods lack the ability to systematically detect structural chromosomal aberrations and identify genes affected by chromosomal breakpoints across tumor samples, particularly in colorectal cancer, limiting the understanding of their impact on tumor progression and clinical behavior.
Innovation Solution
Development of an algorithm, 'GeneBreak', to identify genes recurrently affected by chromosomal SCNA-associated breaks, combined with targeted locus amplification (TLA) and third-generation sequencing to analyze genomic regions surrounding chromosomal breakpoints, enabling the use of these variants as personalized tumor markers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Difficulty of detecting and measuring
If computational methods are used to detect chromosomal aberrations, then detection capability is improved, but the ability to systematically detect structural chromosomal aberrations and identify genes affected by breakpoints deteriorates
Solution Approach 1:
The patent segments the complex task of detecting structural chromosomal aberrations into distinct components: (1) detecting chromosomal breaks using aCGH or WGS data, (2) identifying genes affected by breakpoints through the GeneBreak algorithm, and (3) analyzing recurrent breakpoint patterns across tumor samples. This segmentation enables systematic detection that was previously lacking in computational methods.
Solution Approach 2:
The patent performs preliminary action by first identifying chromosomal breaks and affected genes using the GeneBreak algorithm before conducting further analysis of recurrent patterns. This preliminary identification of breakpoints and affected genes enables subsequent systematic analysis of structural aberrations across multiple samples, resolving the information loss issue.
2Measurement precision
If personalized tumor markers are developed through sequencing genomic regions surrounding chromosomal breakpoints, then measurement precision is improved, but device complexity increases
Solution Approach 1:
The patent extracts and focuses specifically on the genomic regions surrounding chromosomal breakpoints for sequencing analysis. By taking out only the relevant breakpoint regions and flanking sequences rather than sequencing entire genomes, the method achieves high measurement precision for personalized tumor marker identification while reducing the complexity of the sequencing system required.
Solution Approach 2:
The patent applies local quality by concentrating sequencing efforts on specific local regions (breakpoint surroundings) rather than uniform whole-genome sequencing. This localized approach provides high measurement precision for detecting personalized tumor markers at breakpoint locations while minimizing the overall device complexity and sequencing depth required.
3Manufacturing precision
If targeted locus amplification and third-generation sequencing are used to analyze breakpoint regions, then manufacturing precision is improved, but ease of manufacture deteriorates
Solution Approach 1:
The patent performs preliminary action by using targeted locus amplification to pre-enrich and isolate the specific breakpoint regions before sequencing. This preliminary enrichment step ensures high manufacturing precision in the final analysis by concentrating the target sequences, while the standardized TLA protocol makes the overall process more manufacturable despite the additional step.
Data Source
AI summary
The invention relates to methods for tumor marker analysis comprising providing a genomic DNA sample from tumor cells of a patient, preselecting a chromosomal region on the genomic DNA comprising at least part of a potential structural variant (SV); and sequencing the genomic region to characterize the potential SV. The invention further relates to methods for detecting minimal residual disease, monitoring treatment response and tumor progression in a patient by employing the SV, and to personalized therapy based on the identity of the SV.