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Published on: February 6, 2015
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Quantitative functional profiling of ERCC2 mutations deciphers cisplatin sensitivity in bladder cancer
Judit Börcsök1,2, Diyavarshini Gopaul1, Daphne Devesa-Serrano1
1Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
The Journal of Clinical Investigation
|August 19, 2025
Summary
ERCC2 gene mutations in bladder cancer predict cisplatin sensitivity. Functional profiling using CRISPR-Select confirmed these mutations enhance response to platinum-based chemotherapy, aiding precision oncology.
Area of Science:
- Genomics
- Molecular Biology
- Oncology
Background:
- Tumor gene alterations are key predictive biomarkers for therapy response.
- Nucleotide excision repair (NER) helicase ERCC2 mutations occur in ~10% of bladder tumors.
- These ERCC2 mutations may predict sensitivity to cisplatin treatment.
Purpose of the Study:
- To functionally profile ERCC2 mutations for clinical actionability in bladder cancer.
- To assess the impact of heterozygous missense variants in their native context.
- To validate CRISPR-Select as a platform for biomarker discovery.
Main Methods:
- Assembled a multinational cohort of 2,012 bladder cancer patients.
- Applied CRISPR-Select assay to functionally profile recurrent ERCC2 mutations.
- Developed single-allele editing CRISPR-Select for heterozygous variants.
Main Results:
- Identified 506 ERCC2 mutations (93% heterozygous missense).
- CRISPR-Select identified deleterious, cisplatin-sensitizing mutations, especially in helicase domains.
- Single-allele editing showed heterozygous mutations increased cisplatin sensitivity.
- Clinical data integration confirmed improved response to platinum-based neoadjuvant chemotherapy.
Conclusions:
- CRISPR-Select is a robust platform for advancing biomarker-driven therapy in bladder cancer.
- Functional assays are crucial for interpreting mutation effects, outperforming computational predictions.
- Supports integration of CRISPR-Select into precision oncology workflows for bladder cancer treatment.
