NGS Detection of p53 Germ Cell Mutations for Familial Tumor Risk
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Solution Overview
Problem
Current methods lack the ability to effectively determine the risk of developing familial tumors caused by germ cell mutations in the p53 gene, particularly the A159D and D49H mutations, which are rare and understudied, limiting early cancer detection and preventive measures.
Innovation Solution
A method involving next-generation DNA sequencing (NGS) to detect the presence or absence of A159D and D49H mutations in biological samples from test subjects, allowing for the identification of germ cell mutations and their association with familial tumor risk, enabling early cancer detection and preventive measures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If next-generation DNA sequencing (NGS) is used to detect rare p53 mutations, then measurement precision is improved, but device complexity increases
Solution Approach 1:
The patent segments the complex NGS workflow into distinct phases: DNA extraction from biological samples, PCR amplification of p53 gene regions, and sequencing. By dividing the process into manageable segments with standardized protocols for each stage, the system achieves high detection precision for rare mutations while making the overall complex process more controllable and reproducible
Solution Approach 2:
The patent introduces intermediary steps including DNA extraction protocols and PCR amplification as mediators between the biological sample and the NGS system. These intermediaries prepare the sample in a format suitable for sequencing, enabling accurate detection of rare p53 mutations without requiring direct analysis of complex biological materials
2Measurement precision
If comprehensive genome analysis is conducted to identify all SNVs, then measurement precision is improved, but loss of time increases
Solution Approach 1:
The patent applies local quality by focusing analysis resources on specific high-risk regions rather than conducting uniform comprehensive analysis across the entire genome. The methodology prioritizes examination of p53 gene regions and other cancer-associated genes, achieving high detection precision for clinically relevant mutations while significantly reducing the time required compared to whole-genome analysis
Solution Approach 2:
The patent implements partial action by conducting targeted sequencing of specific gene panels (including p53 and other cancer-related genes) rather than complete whole-genome sequencing. This approach provides sufficient detection precision for identifying pathogenic mutations while reducing analysis time and cost, representing an optimal balance between comprehensiveness and efficiency
3Ease of manufacture
If targeted exon analysis is performed to reduce cost, then ease of manufacture is improved, but measurement precision deteriorates
Solution Approach 1:
The patent changes the parameter of sequencing depth and target region selection to optimize the balance between cost and precision. By adjusting these parameters - using appropriate coverage depth for targeted exons and selecting high-priority gene panels - the methodology achieves cost-effective testing that maintains sufficient precision for detecting rare p53 mutations with clinical significance
Data Source
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AI summary
An object of the present invention is to provide a method for predicting a risk of developing cancer. DNA samples were prepared from blood and cancer tissues of 2480 cancer patients and analyzed for the nucleotide sequences of exon regions using NGS. As a result, among the cancer patients, 7 patients were confirmed to have D49H mutation or A159D mutation which is a germ cell mutation.