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Assessing which patients might benefit from DDR-targeting therapy requires knowledge of tumour DDR deficiency (DDRd) status, with mutational signatures reportedly better predictors than loss-of-function mutations. Existing DDRd models offer effective prediction for pathways with well-characterized processes and mutational signatures. Nevertheless, development of models for additional DDRd and clinically relevant mechanisms could be hampered by the fact that most mutational signatures have unknown etiology. Using supervised non-negative matrix factorization (SNMF), we integrate mutational signature learning with multiclass DDR-deficiency prediction to enable etiology-guided learning of signatures from cell lines with confirmed gene knockouts. Applied to DDR gene knockout human-induced pluripotent stem cell lines, SNMF identified etiology-aligned representations of deficiency in homologous recombination, mismatch repair, and base excision repair. Even guided by pathway-level labels, SNMF captured gene-specific base excision repair submechanisms, showing the integration offered added granularity. Learned cell line signatures showed high similarity to tumour-derived COSMIC signatures, revealed associations with mutations in DDR genes, and enabled high recall of tumours with DDR deficiencies. We envision that SNMF-like methods could leverage knockout screens to learn etiology-guided signatures for improved DDRd annotation and treatment optimization. SNMF is available at: https:\/\/github.com\/joanagoncalveslab\/SNMF.<\/jats:p>","DOI":"10.1093\/nargab\/lqag078","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T12:28:49Z","timestamp":1783081729000},"source":"Crossref","is-referenced-by-count":0,"title":["Etiology-guided mutational signature learning from DNA repair knockouts in cell lines using supervised NMF"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7161-0132","authenticated-orcid":false,"given":"Sander","family":"Goossens","sequence":"first","affiliation":[{"name":"Pattern Recognition & Bioinformatics, Intelligent Systems Department, EEMCS Faculty, Delft University of Technology , Van Mourik Broekmanweg 6, 2628 XE Delft ,","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3375-6678","authenticated-orcid":false,"given":"Yasin 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