Tumor-Informed Liquid Biopsy for Tumor Fraction Estimation
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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 calculating variant allele frequencies to determine a reliable circulating tumor fraction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional liquid biopsy assays are used to determine circulating tumor fraction, then the measurement process is simplified, but the accuracy of disease indicator measurement deteriorates due to heterogeneity and chromosomal variations in cancerous tissues
Solution Approach 1:
The assay is divided into distinct modules: a tissue-informed module that identifies patient-specific tumor genomic alterations from solid tumor samples, and a liquid biopsy module that detects these alterations in circulating cell-free DNA. This segmentation allows each module to be optimized independently, improving measurement accuracy while managing overall complexity.
Solution Approach 2:
The method performs preliminary identification of tumor-specific genomic alterations from solid tumor tissue before analyzing liquid biopsy samples. This preliminary action creates a reference profile of tumor mutations that guides the subsequent liquid biopsy analysis, enabling accurate detection of circulating tumor DNA despite tissue heterogeneity and chromosomal variations.
2Reliability
If comprehensive genomic profiling is performed on both solid tumor and liquid biopsy samples, then the classification of variants and detection of copy number variations improve, but the time required for analysis increases
Solution Approach 1:
The method merges the analysis of solid tumor and liquid biopsy samples by using the tumor genomic profile to inform and guide the liquid biopsy interpretation. This integration allows simultaneous achievement of accurate variant classification and copy number variation detection while streamlining the overall analysis process through shared computational resources and unified interpretation frameworks.
Data Source
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.