HLA Allele Copy Number Inference via Intermediary Reference Alignment
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods are unable to accurately determine specific HLA allele copy numbers in tumors, which is crucial for designing effective cancer therapies targeting neoantigens, due to the polymorphic nature of the HLA locus and the limitations of sequence-based methods.
Innovation Solution
A method that aligns HLA allele sequence information with a subject's HLA reference sequence, determines mismatch positions and coverage, and calculates allele frequency to accurately infer HLA allele copy numbers, allowing for the identification of lost or present HLA alleles in tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of time
If sequence-based methods are used to determine HLA allele copy numbers, then the analysis can be performed on historic sequencing information without additional biopsies, but the polymorphic nature of the HLA locus prevents accurate alignment and copy number inference
Solution Approach 1:
The patent introduces an intermediary reference genome approach where reads are first aligned to a reference genome and then lifted over to the HLA locus. This intermediary step enables the use of standard alignment tools while still achieving accurate HLA allele copy number determination by bridging the gap between reference-based alignment and polymorphic HLA sequence variation.
2Measurement precision
If antibody-based methods are used to detect HLA type, then specific HLA allele expression can be analyzed, but the methods are labour intensive and costly
Solution Approach 1:
The patent replaces the mechanical/chemical antibody-based detection system with a computational sequence-based method. Instead of using physical antibodies to bind and detect HLA alleles, the invention uses bioinformatics algorithms to align sequencing reads and infer allele copy numbers, thereby eliminating the need for labor-intensive wet lab procedures while maintaining detection accuracy.
3Ease of manufacture
If standard alignment methods are used on HLA sequences, then reads can be mapped to the reference genome, but the polymorphic nature of the HLA locus prevents accurate copy number inference
Solution Approach 1:
The patent segments the analysis into distinct computational steps: first aligning reads to the reference genome using standard tools, then separately performing HLA-specific allele calling and copy number inference. This segmentation allows each step to be optimized independently, maintaining the simplicity of standard alignment while achieving precise copy number determination through specialized downstream analysis.
Data Source
AI summary
The present invention relates to a method for determining whether an HLA allele is lost in a tumour in a subject, wherein said method comprises the step of determining the specific copy number of said HLA allele in said tumour. The invention also relates to a method for treating cancer in a subject, comprising targeting a neoantigen which is predicted to be presented by an HLA molecule encoded by an HLA allele which has been determined not to have been lost in a tumour in said subject.