Tumor DNA Profiling for HR-Deficiency Classification
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Solution Overview
Problem
Current methods struggle to effectively classify DNA samples from tumors to determine homologous recombination (HR) deficiency, which is crucial for personalized cancer treatment strategies, particularly in identifying BRCA1/2-deficient cancers.
Innovation Solution
A method and computer-implemented approach to characterize DNA samples by determining the presence of base substitution, rearrangement, and indel signatures, along with copy number profiles, generating a probabilistic score to identify HR-deficiency, using weighted factors such as microhomology-mediated indels and HRD index.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If multiple genomic parameters (base substitution signatures, rearrangement signatures, indel signatures, copy number profiles) are analyzed to improve HR-deficiency classification accuracy, then measurement precision improves, but device complexity increases
Solution Approach 1:
The method segments the complex task of HR-deficiency classification into distinct analytical components: base substitution signature analysis, rearrangement signature analysis, indel signature analysis, and copy number profile analysis. Each component is evaluated separately and then integrated through a probabilistic scoring system, making the overall complex process more manageable and interpretable while maintaining high classification accuracy
Solution Approach 2:
The method transforms multiple genomic parameters (presence/absence of various mutation signatures and copy number profiles) into a unified probabilistic score that quantifies HR-deficiency likelihood. This parameter transformation allows complex multi-dimensional genomic data to be converted into a single interpretable metric that maintains measurement precision while simplifying clinical interpretation
2Reliability
If comprehensive genomic profiling is performed to enable personalized treatment selection, then treatment efficacy improves, but loss of time increases
Solution Approach 1:
The method performs preliminary analysis by pre-defining and weighting multiple genomic parameters that are known to be associated with HR-deficiency. By establishing the analytical framework and probability weightings in advance, the method enables rapid application to new patient samples without requiring de novo development of analysis protocols, thus reducing time loss while maintaining comprehensive profiling
Solution Approach 2:
The method generates a probabilistic score that provides immediate feedback on HR-deficiency likelihood, enabling clinicians to quickly assess treatment suitability. This quantitative feedback mechanism allows for rapid treatment decision-making while maintaining comprehensive genomic analysis, as the probabilistic output directly guides therapeutic selection without requiring additional time-consuming interpretation steps
Data Source
AI summary
The invention provides a method of characterising a DNA sample obtained from a tumour, the method including the steps of: determining the presence or absence of a plurality of base substitution signatures, rearrangement signatures and indel signatures in the sample and copy number profiles for the sample; generating, from the presence or absence of said plurality of base substitution signatures, rearrangement signatures and indel signatures and the copy number profile for the sample, a probabilistic score; and based on said probabilistic score, identifying whether said sample has a high or low likelihood of being homologous recombination (HR)-deficient. Identification of a tumour as HR-deficient may be used to inform treatment choices, for example treatment with a PARP inhibitor or platinum therapy or an anthracycline.