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Although mutational signatures are most commonly derived from whole exome (WES) or whole genome sequencing (WGS) data, more patients currently undergo tumor sequencing using more limited targeted panels that typically encompass several hundred cancer-associated genes. Identifying clinically relevant mutational signatures from targeted panel data requires new approaches capable of deriving signatures from the more limited sequencing data. Here, we derive and validate a panel sequencing-based composite mutational signature associated with nucleotide excision repair (NER) deficiency induced by inactivating\n                  <jats:italic>ERCC2<\/jats:italic>\n                  mutations in bladder cancer. Using publicly available panel sequencing data, we find that\n                  <jats:italic>ERCC2<\/jats:italic>\n                  wild type (WT) bladder cancer cases that have high levels of this mutational signature respond better to neoadjuvant platinum therapy and have improved overall survival compared to\n                  <jats:italic>ERCC2<\/jats:italic>\n                  WT cases with low levels of the signature. We also find that other solid tumor types with\n                  <jats:italic>ERCC2<\/jats:italic>\n                  mutations also show the characteristic mutational signature seen in NER-deficient\n                  <jats:italic>ERCC2<\/jats:italic>\n                  -mutant bladder cancers, suggesting a novel approach to therapeutically target these\n                  <jats:italic>ERCC2<\/jats:italic>\n                  -mutant solid tumors beyond bladder cancer.\n                <\/jats:p>","DOI":"10.64898\/2026.02.17.706196","type":"posted-content","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T15:10:13Z","timestamp":1771513813000},"source":"Crossref","is-referenced-by-count":0,"title":["Identification of an\n                  <i>ERCC2<\/i>\n                  mutation associated mutational signature of nucleotide excision repair deficiency in targeted panel sequencing data"],"prefix":"10.64898","author":[{"given":"Olivera","family":"Stojkova","sequence":"first","affiliation":[{"name":"Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"B\u00f6rcs\u00f6k","sequence":"additional","affiliation":[{"name":"Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark"},{"name":"Translational Cancer Genomics Group, Danish Cancer Institute, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zsofia","family":"Sztupinszki","sequence":"additional","affiliation":[{"name":"Translational Cancer Genomics Group, Danish Cancer Institute, Copenhagen, Denmark"},{"name":"Computational Health Informatics Program, Boston Children\u2019s Hospital, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miklos","family":"Diossy","sequence":"additional","affiliation":[{"name":"Computational Health Informatics Program, Boston Children\u2019s Hospital, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aurel","family":"Prosz","sequence":"additional","affiliation":[{"name":"Translational Cancer Genomics Group, Danish Cancer Institute, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Neil","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kent W.","family":"Mouw","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA"},{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA"},{"name":"Harvard Medical School, Boston, 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