HRD Status Determination via SNP LOH Scoring
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Solution Overview
Problem
Current methods for assessing homologous recombination deficiency (HRD) status in patients are limited, with only two companion diagnostic tests approved for PARP inhibitor treatment, necessitating the development of more effective assays to identify patients who would benefit from this therapy.
Innovation Solution
A method involving sequencing of single nucleotide polymorphism (SNP) loci to calculate a loss of heterozygosity (LOH) score, which determines the HRD status by assessing the ratio of LOH SNP loci to non-homozygous SNP loci, utilizing next-generation sequencing (NGS) platforms and specific gene analysis, including BRCA1/2 and other HRR-associated genes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If only two FDA-approved companion diagnostic tests (Myriad myChoice and Foundation Focus) are used for HRD status determination, then the assay complexity is limited, but the comprehensiveness and accuracy of HRD assessment is insufficient
Solution Approach 1:
The patent segments the HRD assessment into multiple independent components: (1) sequencing of multiple SNP loci across the genome, (2) calculation of LOH scores based on loss of heterozygosity, (3) evaluation of multiple genomic features including copy number variations and mutational signatures, and (4) integration of these features to determine overall HRD status. This segmentation allows for comprehensive assessment while maintaining manageable assay complexity through modular analysis steps.
Solution Approach 2:
The patent employs next-generation sequencing technology that serves multiple functions: it sequences SNP loci for LOH detection, identifies copy number variations, detects mutational signatures, and provides comprehensive genomic profiling. This multi-functional approach consolidates multiple diagnostic capabilities into a single platform, improving assessment accuracy without proportionally increasing assay complexity.
2Reliability
If comprehensive genomic sequencing is performed to accurately assess HRD status, then the assessment comprehensiveness is improved, but the cost and time required for testing increases
Solution Approach 1:
The patent performs preliminary bioinformatics processing and filtering of sequencing data to identify only the most relevant genomic features associated with HRD status. By pre-defining the analytical pipeline to focus on key markers such as LOH regions, specific mutational signatures, and copy number variation patterns, the method reduces the time required for data analysis while maintaining comprehensive assessment reliability.
Solution Approach 2:
The patent replaces manual or step-by-step manual analysis methods with automated bioinformatics pipelines and computational algorithms that process sequencing data efficiently. This substitution of computational automation for manual analysis significantly reduces testing time while maintaining or improving the reliability of HRD status determination through consistent and reproducible analysis.
3Measurement precision
If more SNP loci are sequenced to improve LOH score accuracy, then the measurement precision is improved, but the manufacturing complexity and data processing burden increases
Solution Approach 1:
The patent applies local quality control by selectively analyzing SNP loci based on their informational value for LOH detection. Rather than uniformly processing all possible SNPs, the method focuses on loci that are most informative for detecting loss of heterozygosity events, using local genomic context and variant allele frequency thresholds to prioritize analysis. This approach improves LOH score accuracy while reducing data processing complexity by concentrating resources on high-value loci.
Data Source
AI summary
The present disclosure provides a method, a system and a kit for assessing the homologous recombination deficiency (HRD) status of a subject. The present disclosure further provides a method, a system and a kit for identifying a treatment based on the HRD status for the human subject.