Liquid Biopsy cfDNA Size Segmentation for Cancer Genomic Detection
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Solution Overview
Problem
Current methods for detecting and monitoring allele-specific copy number aberrations in cancers, particularly prostate cancer, face challenges due to low tumor DNA fractions, intra-patient genomic heterogeneity, and imbalanced copy number changes, leading to inaccurate detection of genomic lesions and limited information on genetic aberrations.
Innovation Solution
An in vitro method and assay utilizing a selected panel of high MAF SNP loci in exonic, intronic, and flanking regions of specific genes to detect allele-specific copy number aberrations, providing detailed information on complex aberrations and allowing for real-time monitoring of treatment effectiveness.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If liquid biopsies are used to detect genomic aberrations in cancer patients, then non-invasive monitoring and comprehensive tumor characterization are enabled, but detection accuracy deteriorates due to low ctDNA fractions and high background noise from normal cfDNA
Solution Approach 1:
The method segments the cfDNA population by size, isolating smaller DNA fragments (0.1-10 kb) that are enriched for tumor-derived material. This size-based segmentation increases the proportion of ctDNA in the analyzed sample, thereby improving detection accuracy while maintaining the non-invasive liquid biopsy approach.
Solution Approach 2:
The invention applies local quality enhancement by specifically targeting and enriching the size fraction of cfDNA most likely to contain tumor information. By focusing analysis on smaller DNA fragments with higher tumor enrichment, the method improves local detection sensitivity without requiring invasive procedures.
2Loss of information
If comprehensive genomic analysis is performed on all cfDNA, then complete tumor characterization is achieved, but detection sensitivity deteriorates due to overwhelming background from normal DNA
Solution Approach 1:
The method extracts the tumor-relevant signal from the background of normal cfDNA by isolating smaller DNA fragments that are enriched for tumor content. This extraction process removes the overwhelming normal DNA background while retaining the tumor genomic information, thereby improving the signal-to-noise ratio without losing comprehensive tumor characterization capability.
3Ease of manufacture
If archival tissue biopsies are used for biomarker assessment, then treatment selection is enabled, but reliability deteriorates due to temporal and spatial limitations
Solution Approach 1:
The invention transitions from static archival tissue biopsy to dynamic liquid biopsy monitoring. By enabling serial sampling of cfDNA over time, the method provides ongoing, updated information about tumor genetics, ensuring that treatment decisions are based on current disease state rather than historical tissue samples that may no longer represent the tumor.
4Quantity of substance
If copy number changes are detected in low ctDNA fraction samples, then comprehensive genomic profiling is achieved, but measurement precision deteriorates due to insufficient tumor signal
Solution Approach 1:
The method introduces a new dimension for differentiation - DNA fragment size - which is not typically used in conventional genomic analysis. By analyzing cfDNA in size-resolved fractions, the invention enables accurate copy number detection in low ctDNA samples, as the smaller size fraction contains enriched tumor material that provides sufficient signal even when overall ctDNA fraction is low.
Data Source
AI summary
The present invention provides an in vitro method, and in vitro assay, for staging, classification, screening, monitoring, stratification, selecting treatment for, ascertaining whether treatment is working in, and/or prognostication of cancer in a subject comprising determining allelic imbalance and copy number of target gene-regions in tumor DNA from a subject as set out in the application. The present invention also provides a set of oligonucleotide probes and kits for use in the method, and assay, of the present invention.