Quantitative functional profiling of ERCC2 mutations deciphers cisplatin sensitivity in bladder cancer Journal Article
| Authors: | Borcsok, J.; Gopaul, D.; Devesa-Serrano, D.; Mooser, C.; Jonsson, N.; Cagiada, M.; Stormoen, D. R.; Ataya, M. N.; Guercio, B. J.; Kaimakliotis, H. Z. |
| Article Title: | Quantitative functional profiling of ERCC2 mutations deciphers cisplatin sensitivity in bladder cancer |
| Abstract: | Tumor gene alterations can serve as predictive biomarkers for therapy response. The nucleotide excision repair (NER) helicase ERCC2 carries heterozygous missense mutations in approximately 10% of bladder tumors, and these may predict sensitivity to cisplatin treatment. 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. This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine |
| Keywords: | aged; middle aged; genetics; missense mutation; mutation, missense; cisplatin; metabolism; dna repair; neoplasm proteins; drug resistance; drug resistance, neoplasm; oncology; bladder tumor; urinary bladder neoplasms; tumor protein; urology; drug therapy; cell biology; xeroderma pigmentosum group d protein; cancer; humans; human; male; female; ercc2 protein, human |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 135 |
| Issue: | 16 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2025-01-01 |
| Language: | English |
| DOI: | 10.1172/jci186688 |
| PUBMED: | 40829180 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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