Solid-Tumor Profiling and VAF Analysis for Circulating Tumor Fraction
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Solution Overview
Problem
Conventional liquid biopsy assays face challenges in accurately determining the circulating tumor fraction due to heterogeneity and chromosomal variations in cancerous tissues, leading to inaccurate measurement of disease indicators and actionable genomic alterations.
Innovation Solution
A method combining tissue-informed, comprehensive genomic profiling with non-bespoke blood-based profiling to estimate circulating tumor fraction using targeted-panel sequencing, which includes obtaining nucleic acid sequences from both solid tumor and liquid biopsy samples, identifying somatic mutations, and determining variant allele frequencies to improve accuracy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional liquid biopsy assays are used to determine circulating tumor fraction, then the procedure is minimally invasive and cost-effective, but the measurement accuracy is poor due to heterogeneity and chromosomal variations in cancerous tissues
Solution Approach 1:
The assay is divided into two distinct parts: (1) tissue-informed comprehensive genomic profiling of solid tumor samples to identify patient-specific somatic mutations, and (2) blood-based profiling to measure variant allele frequencies. This segmentation allows each part to be optimized independently, improving measurement accuracy while maintaining procedural simplicity.
Solution Approach 2:
The method performs preliminary comprehensive genomic profiling on solid tumor samples before conducting the liquid biopsy. This preliminary action identifies patient-specific somatic mutations that serve as reference points for accurate circulating tumor fraction measurement in the blood sample, thereby improving measurement accuracy.
2Reliability
If comprehensive genomic profiling is performed on solid tumor samples, then the identification of somatic mutations is improved, but the invasiveness and cost of the procedure increase
Solution Approach 1:
The solid tumor sample acts as an intermediary that provides patient-specific genomic information without requiring direct analysis of the circulating tumor cells. By using the tumor sample to identify somatic mutations, which then serve as markers in the blood-based assay, the method achieves high reliability while minimizing patient invasiveness.
Solution Approach 2:
The method creates a genomic copy of the patient's tumor DNA through comprehensive profiling, then uses this information to guide the liquid biopsy analysis. This copying approach allows accurate somatic mutation identification from the tumor sample to be applied to the blood-based assay, improving reliability without requiring direct tumor cell analysis in the circulating blood.
3Measurement precision
If targeted-panel sequencing is used to estimate circulating tumor fraction, then the assay becomes more accurate in detecting genomic alterations, but the complexity of data analysis increases
Solution Approach 1:
The assay focuses analysis on specific patient-specific somatic mutations identified from the tumor sample, rather than attempting to analyze all possible genomic alterations. This local quality approach concentrates computational resources on relevant variants, improving detection accuracy while reducing overall data analysis complexity.
Solution Approach 2:
The tissue-informed component provides feedback about patient-specific somatic mutations that guides the blood-based profiling analysis. This feedback mechanism allows the assay to focus on clinically relevant variants, improving genomic alteration detection accuracy while simplifying data interpretation through patient-specific mutation filtering.
Data Source
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AI summary
Methods, systems, and software for estimating circulating tumor fraction are provided. A first plurality of nucleic acid sequences for a plurality of loci in genomic DNA from a solid tumor sample is obtained. A second plurality of nucleic acid sequences for a plurality of cell-free DNA fragments obtained from a liquid biopsy sample from the same subject is obtained. One or more somatic mutations is identified in the first plurality of nucleic acid sequences. A variant allele frequency (VAF) is determined for each somatic mutation based on a frequency of the respective somatic mutation in the liquid biopsy sample and a frequency of the corresponding wild type allele in the liquid biopsy sample, thereby determining a set of VAFs. An estimate of the circulating tumor fraction for the test subject is determined based on the set of VAFs for the one or more somatic mutations.