Mutational Signature Filtering for Tumour-Informed Variant Selection
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Solution Overview
Problem
Existing cancer treatment methods fail to accurately distinguish between genuine somatic genetic variants associated with residual cancer cells and artefactual mutations introduced by sample processing or therapy, leading to reduced assay sensitivity in detecting minimal residual disease (MRD).
Innovation Solution
A method utilizing mutational signature analysis to filter and select a set of genetic variants most likely to be present in a tumour, by aligning a mutational catalogue from a patient's sample with a database of cancer-specific mutational signatures, excluding artefactual variants, and prioritizing those associated with the cancer type.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If a tumour-informed assay uses genetic variants from sequencing, then it can detect minimal residual disease, but it includes false positives from artefactual mutations introduced by sample processing or therapy
Solution Approach 1:
The patent extracts and removes artefactual mutations from the set of detected genetic variants by comparing them against known mutational signatures. This separation isolates genuine somatic variants from false positives introduced by processing, thereby improving detection accuracy while reducing false positive rate
Solution Approach 2:
The patent introduces mutational signatures as an intermediary reference framework. By aligning observed variants against this intermediary database of known mutational patterns, the system can distinguish between true cancer-related variants and artefactual ones, resolving the contradiction between detection sensitivity and false positive reduction
2Productivity
If the assay includes all observed genetic variants, then it maximizes detection coverage, but it reduces sensitivity by including artefactual variants
Solution Approach 1:
The patent applies local quality filtering by evaluating each genetic variant individually against mutational signatures. Instead of uniformly treating all variants equally, the system assigns different weights and inclusion criteria based on whether each variant matches expected cancer-related mutational patterns, thereby maintaining detection coverage while improving sensitivity
Solution Approach 2:
The patent changes the parameter of variant selection from a simple count-based approach to a probability-based approach using mutational signature alignment. By transforming the selection criterion from 'all observed variants' to 'variants matching mutational signatures with probability threshold', the system simultaneously achieves high detection coverage and sensitivity
Data Source
AI summary
Methods and apparatus for selecting genetic variants for a tumour-informed assay are provided. The method includes receiving a sample collected from a patient, the sample being associated with a cancer type, generating a mutational catalogue for the sample, the mutational catalogue indicating a proportion of genetic mutation types observed in the sample, selecting a set of signatures associated with the cancer type, the set including one or more signatures, each signature comprising a mutational profile, determining, based on the set of signatures associated with the cancer type and the mutational catalogue, a set of genetic variants most likely to be genuine somatic variants associated with the sample, and outputting the set of genetic variants for use in creating a tumour-informed assay for the patient.