Chromosomal Instability Characterization via Copy Number Signatures
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Solution Overview
Problem
Current methods lack a systematic framework to comprehensively characterize the diversity, extent, and origins of chromosomal instability (CIN) in cancers, and to define how different types of CIN relate to clinical phenotypes.
Innovation Solution
A robust analysis framework that characterizes CIN using a limited set of fundamental copy number features, excluding absolute copy number, to identify patterns of chromosomal instability across 33 cancer types, supported by independent data sources.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current CIN characterization methods are used, then analysis can be performed with existing tools, but the methods cannot comprehensively characterize the diversity, extent and origins of CIN
Solution Approach 1:
The patent segments CIN characterization into distinct mutational signatures (e.g., SBS1, SBS2, SBS3, SBS4, SBS5, SBS6, SBS7, SBS8, SBS9, SBS10, SBS11, SBS12, SBS13, SBS14, SBS15, SBS16, SBS17, SBS18, SBS19, SBS20, SBS21, SBS22, SBS23, SBS24, SBS25, SBS26, SBS27, SBS28, SBS29, SBS30, SBS31, SBS32, SBS33, SBS34, SBS35, SBS36, SBS37, SBS38, SBS39, SBS40, SBS41, SBS42, SBS43, SBS44, SBS45, SBS46, SBS47, SBS48, SBS49, SBS50, SBS51, SBS52, SBS53, SBS54, SBS55, SBS56, SBS57, SBS58, SBS59, SBS60, SBS61, SBS62, SBS63, SBS64, SBS65, SBS66, SBS67, SBS68, SBS69, SBS70, SBS71, SBS72, SBS73, SBS74, SBS75, SBS76, SBS77, SBS78, SBS79, SBS80, SBS81, SBS82, SBS83, SBS84, SBS85, SBS86, SBS87, SBS88, SBS89, SBS90, SBS91, SBS92, SBS93, SBS94, SBS95, SBS96, SBS97, SBS98, SBS99, SBS100) that represent different mutational processes. Each signature is characterized by specific patterns of copy number alterations, allowing comprehensive CIN characterization through composition of these discrete signature components rather than treating CIN as a monolithic phenomenon.
Solution Approach 2:
The patent changes the parameters used to characterize CIN from traditional metrics (overall CIN level, specific chromosomal abnormalities) to a signature-based parameter system. Each mutational signature is defined by parameters including the set of copy number alterations it produces, its contribution weight to the overall CIN profile, and its association with specific mutational processes. This parameter transformation enables precise quantification of different CIN types and their relative contributions.
2Loss of information
If comprehensive CIN characterization is achieved, then different types of CIN can be distinguished, but the methods become too complex for systematic analysis
Solution Approach 1:
The patent creates simplified copy models of complex CIN processes by representing each mutational signature as a reproducible pattern of copy number alterations. These signature copies can be systematically applied and combined to reconstruct observed CIN profiles, enabling complex CIN diversity to be analyzed through repeated application of standardized signature units rather than requiring direct analysis of each unique CIN manifestation.
Solution Approach 2:
The patent develops a universal signature framework that can characterize multiple types of CIN (whole-chromosome CIN, arm-level CIN, focal CIN) using the same set of mutational signatures. The framework is multi-functional, capable of analyzing different cancer types, different CIN scales, and different mutational processes through a single unified approach, eliminating the need for separate characterization methods for each CIN type.
3Measurement precision
If traditional CIN measures are used, then broad categorization is achieved, but specific aetiologies like homologous repair deficiency cannot be identified
Solution Approach 1:
The patent applies local quality by associating specific mutational signatures with specific aetiologies and genomic contexts. Each signature is characterized by its local properties including the specific copy number alterations it produces, the genomic regions it affects, and its association with particular DNA repair deficiencies. This allows precise identification of aetiologies like homologous repair deficiency by detecting the characteristic local signature patterns rather than requiring global CIN assessment.
Data Source
AI summary
A method of characterising a DNA sample obtained from a tumour, the method including the steps of: (a) obtaining a tumour copy number profile for the sample, (b) quantifying a set of copy number features of the copy number profile, and (c) determining exposure to one or more signatures of chromosomal instability based on the quantified features. A copy number feature is a metric that characterises a copy number event in a copy number profile. The set of features does not comprise the absolute copy number of segments in the copy number profile. The signatures of chromosomal instability have been obtained by quantifying the set of copy number features in a plurality of tumour samples, and identifying one or more mutational signatures likely to result in the copy number profiles of the plurality of tumour samples. Methods of characterising types of chromosomal instability present in samples, providing a prognosis, identifying a drug target, or identifying a therapy for a subject are also described.