Universal Oligonucleotide Pool for Cancer DNA Sequencing
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Solution Overview
Problem
Current methods for detecting minimal residual disease (MRD) in cancer patients are not sensitive enough, as they struggle to detect low frequencies of cancer-specific variants in cell-free DNA due to sequencing artifacts and high costs associated with synthesizing patient-specific oligonucleotide primer panels, limiting the scalability of existing techniques.
Innovation Solution
The use of a large pool of oligonucleotides that can target multiple patients, allowing for the selective sequencing of cancer-specific variants, where subsets of the pool are used to enrich specific regions of interest, reducing the need for individual patient-specific primer panels and lowering costs through economies of scale.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If patient-specific oligonucleotide primer panels are synthesized for each patient to detect cancer-specific variants, then detection sensitivity for minimal residual disease is improved, but manufacturing cost increases significantly
Solution Approach 1:
The patent creates a universal pool of oligonucleotides that can target multiple patients' cancer variants simultaneously. Instead of synthesizing separate patient-specific panels, a single multi-purpose pool serves multiple patients by containing oligonucleotides with different patient-specific identifier sequences, thereby reducing manufacturing costs while maintaining detection sensitivity
Solution Approach 2:
The universal oligonucleotide pool is segmented into patient-specific sub-populations based on identifier sequences. Each patient's sample is processed by selecting and amplifying only the oligonucleotides matching their specific identifiers, allowing one pool to function as multiple patient-specific panels without synthesizing separate pools for each patient
2Measurement precision
If the number of variants targeted per patient is increased to increase sensitivity 50× to 1000×, then detection sensitivity is improved, but the cost of synthesizing patient-specific oligonucleotide primer panels becomes prohibitive
Solution Approach 1:
The patent merges multiple patient-specific oligonucleotide panels into a single universal pool. By combining oligonucleotides targeting variants from many patients into one pool, the system achieves high sensitivity (tracking thousands of variants) without multiplying synthesis costs, as the pool is synthesized once and shared across patients
Solution Approach 2:
Instead of synthesizing unique oligonucleotide sequences for each patient, the system uses a master pool that contains replicated sequences for multiple patients. The patient-specific information is encoded in identifier sequences within the pool, allowing computational differentiation without physical replication of entire panels
3Ease of manufacture
If conventional sequencing methods are used to detect cancer DNA in cfDNA, then the methodology is simple and cost-effective, but detection sensitivity is insufficient due to sequencing artifacts and low frequency of tumor variants
Solution Approach 1:
The patent introduces an intermediary enrichment step using patient-specific oligonucleotides from the universal pool to capture and concentrate cancer-specific variants before sequencing. This intermediary step separates rare tumor DNA from abundant normal DNA and from sequencing artifacts, enabling conventional sequencing methods to achieve high sensitivity by focusing only on enriched target regions
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach significantly increases the sensitivity and cost-effectiveness of detecting MRD, enabling the detection of cancer DNA at very low variant allele frequencies while reducing the financial burden of synthesizing large numbers of patient-specific oligonucleotides.
Implementation Method 1
each member of the first sub-population of oligonucleotides comprises a first sequence that is complementary to one of the plurality of target regions from the first patient
Data Source
AI summary
A method for selective sequencing of a plurality of target regions from a patient is provided. A pool of oligonucleotides comprises a first sub-population targeting the plurality of target regions and a second sub-population. Each member of the first sub-population of oligonucleotides comprises a first sequence that is complementary to one of the plurality of target regions from the patient and an identifier sequence specific to the patient, and each member of the second sub-population of oligonucleotides comprises a first sequence that is complementary to one of the plurality of target regions from a second patient and an identifier sequence specific to the second patient. A test sample from the patient is contacted with the pool, and then contacted with oligonucleotides comprising a sequence that is complementary to the identifier sequence specific to the first patient. The plurality of target regions from the patient are then selected and sequenced.