CTCF Binding Region Analysis in Cell-Free DNA

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Solution Overview

Problem

Current liquid biopsy tests for cancer diagnosis face challenges in detecting tumor-originating somatic mutations in plasma cell-free DNA (cfDNA) due to the small amount of tumor DNA present, especially in early-stage cancer, making it difficult to achieve sensitive and accurate results.

Innovation Solution

The method involves analyzing the fragmentation pattern of cfDNA in plasma, specifically at CTCF binding regions, to detect nucleosomal organization patterns that are tissue-specific, allowing for the amplification of tumor DNA signals and differentiation from normal tissues, using computer-processed distributions to identify genetic aberrations and classify clinical cohorts.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If liquid biopsy tests analyze tumor-originating somatic mutations in plasma cfDNA, then cancer diagnosis and prognosis can be achieved, but the detection sensitivity is insufficient when tumor DNA amount is very small

Engineering Contradiction:

Improvedetection sensitivityVSAvoidtumor DNA amount

Core Design Contradiction:

Measurement precisionVSQuantity of substance

Solution Approach 1:

The patent uses nucleosomal organization patterns as an intermediary signal to detect tumor DNA. Instead of directly detecting tumor DNA sequences, the method analyzes how nucleosomes are organized around CTCF binding sites, which serves as a mediator that amplifies the detectable signal from tumor DNA even when its quantity is very low.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the detection parameter from direct DNA sequence analysis to nucleosomal organization pattern analysis. By measuring fragment length distributions and cleavage point patterns around CTCF binding regions, the method transforms the detection approach to one that is sensitive to chromatin structure changes caused by tumor DNA, enabling detection even when tumor DNA amount is minimal.

Inventive Principle:

Principle #35Parameter changes

2Measurement precision

If liquid biopsy tests rely on somatic mutation detection in cfDNA, then cancer genetic information can be obtained, but the accuracy is compromised when tumor DNA concentration is low

Engineering Contradiction:

Improvedetection accuracyVSAvoidtumor DNA concentration

Core Design Contradiction:

Measurement precisionVSQuantity of substance

Solution Approach 1:

The patent adds a new dimension to DNA analysis by examining nucleosomal organization patterns and chromatin structure around CTCF binding sites. This dimensional shift from sequence-only analysis to structure-aware analysis provides additional information that improves detection accuracy, allowing the system to distinguish tumor DNA from normal DNA based on chromatin organization differences even when tumor DNA concentration is low.

Inventive Principle:

Principle #17Another dimension (Dimensionality change)

Solution Approach 2:

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If liquid biopsy tests analyze all cfDNA in plasma, then comprehensive genetic information can be obtained, but the tumor-specific signal is diluted by normal tissue DNA

Engineering Contradiction:

ImprovecfDNA signalVSAvoidtumor signal dilution

Core Design Contradiction:

Quantity of substanceVSLoss of information

Solution Approach 1:

The patent applies local quality by focusing analysis specifically on CTCF binding regions where nucleosomal organization patterns are highly tissue-specific. By concentrating computational and analytical resources on these particular genomic loci rather than analyzing all cfDNA uniformly, the method enhances the tumor-specific signal while filtering out background noise from normal tissue DNA.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent segments the cfDNA analysis by focusing on specific genomic regions (CTCF binding sites) rather than analyzing the entire genome uniformly. This segmentation allows the method to concentrate on regions where tumor and normal DNA exhibit distinct nucleosomal organization patterns, thereby improving signal-to-noise ratio and reducing dilution effects.

Inventive Principle:

Principle #1Segmentation

4Reliability

If liquid biopsy tests use traditional mutation detection methods, then standard cancer markers can be identified, but the sensitivity for early-stage cancer is insufficient

Engineering Contradiction:

Improvecancer detection reliabilityVSAvoidtumor DNA amount in early-stage cancer

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent replaces the mechanical approach of direct DNA sequence detection with a bio-physical approach that analyzes nucleosomal organization and chromatin structure. By substituting sequence-based detection with structure-based detection, the method achieves higher sensitivity for early-stage cancer where tumor DNA amounts are extremely low, as chromatin structure patterns provide amplified signals that are more detectable than rare sequence variants.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS20210125685A1Methods and systems for analysis of CTCF binding regions in cell-free DNA

Publication Date: 2021.04.29 GUARDANT HEALTH INC

AI summary

The present disclosure provides systems and methods to analyze CTCF binding regions in cell-free DNA (cfDNA) from a subject to detect tumor-originating cfDNA.