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To explore the clinical actionability of ERCC2 mutations, we assembled a multinational cohort of 2,012 individuals with bladder cancer and applied the highly quantitative CRISPR-Select assay to functionally profile recurrent ERCC2 mutations. We also developed a single-allele editing version of CRISPR-Select to assess heterozygous missense variants in their native context. From the cohort, 506 ERCC2 mutations were identified, with 93% being heterozygous missense variants. CRISPR-Select pinpointed deleterious, cisplatin-sensitizing mutations, particularly within the conserved helicase domains. Importantly, single-allele editing revealed that heterozygous helicase-domain mutations markedly increased cisplatin sensitivity. Integration with clinical data confirmed that these mutations were associated with improved response to platinum-based neoadjuvant chemotherapy. Comparison with computational algorithms showed substantial discrepancies, highlighting the importance of precision functional assays for interpreting mutation effects in clinically relevant contexts. Our results demonstrate that CRISPR-Select provides a robust platform to advance biomarker-driven therapy in bladder cancer and supports its potential integration into precision oncology workflows.<\/jats:p>","DOI":"10.1172\/jci186688","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T16:49:08Z","timestamp":1755535748000},"source":"Crossref","is-referenced-by-count":14,"title":["Quantitative functional profiling of ERCC2 mutations deciphers cisplatin sensitivity in bladder cancer"],"prefix":"10.1172","volume":"135","author":[{"given":"Judit","family":"B\u00f6rcs\u00f6k","sequence":"first","affiliation":[{"name":"Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark."},{"name":"Translational Cancer Genomics Group, Danish Cancer Institute, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diyavarshini","family":"Gopaul","sequence":"additional","affiliation":[{"name":"Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne","family":"Devesa-Serrano","sequence":"additional","affiliation":[{"name":"Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9mence","family":"Mooser","sequence":"additional","affiliation":[{"name":"Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Jonsson","sequence":"additional","affiliation":[{"name":"Linderstr\u00f8m-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Cagiada","sequence":"additional","affiliation":[{"name":"Linderstr\u00f8m-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dag R.","family":"Stormoen","sequence":"additional","affiliation":[{"name":"Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya N.","family":"Ataya","sequence":"additional","affiliation":[{"name":"Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan J.","family":"Guercio","sequence":"additional","affiliation":[{"name":"Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA."},{"name":"James P. 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