{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T07:59:46Z","timestamp":1790323186512,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,21]]},"group-title":"Bioinformatics","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["R01CA269805"],"award-info":[{"award-number":["R01CA269805"]}]},{"name":"NIH","award":["R01HG012573"],"award-info":[{"award-number":["R01HG012573"]}]},{"name":"NIH","award":["UM1DA058230"],"award-info":[{"award-number":["UM1DA058230"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Somatic mutations in cancer genomes record the activities of diverse mutational processes. Mutational signature analysis has advanced mechanistic understanding of mutagenesis and informed clinical decision-making, yet existing methods assume independence among signatures\u2014an unrealistic assumption that can produce composite or contaminated signatures, reduce detection power, and yield inconsistent results. Here we present Cornet (CORrelated NMF ExTraction), a framework for mutational signature discovery that explicitly models co-occurring processes and jointly infers signatures and their correlation structure. Benchmarking on simulated data shows Cornet more accurately recovers distinct signatures under strong correlations. Applied to cancer genomes, Cornet enables unsupervised discovery of the colibactin-associated signature SBS88 in oral cancers and identifies the tobacco smoking signature SBS4 in bladder cancer, where it was previously thought absent. Cornet also uncovers a novel mutational process implicated in early-onset colorectal cancer and a signature arising from the interplay between tobacco smoking and ERCC2-mutation-driven nucleotide-excision repair deficiency. Together, these results demonstrate that modeling correlations among mutational processes is essential for high-resolution signature discovery and dissecting the mutational etiology of human cancer.<\/jats:p>","DOI":"10.64898\/2026.09.14.751548","type":"posted-content","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:20:17Z","timestamp":1790004017000},"source":"Crossref","is-referenced-by-count":0,"title":["Correlation-aware discovery of co-occurring mutational signatures in cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8657-5686","authenticated-orcid":false,"given":"Hu","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1854-3428","authenticated-orcid":false,"given":"Benedikt","family":"Geiger","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8112-9073","authenticated-orcid":false,"given":"Dominik","family":"Glodzik","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5419-0549","authenticated-orcid":false,"given":"Doga C","family":"Gulhan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA"},{"name":"Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9378-960X","authenticated-orcid":false,"given":"Peter J","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"5","key":"2026092500100928000_2026.09.14.751548v1.1","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/s41576-021-00431-y","article-title":"Computational analysis of cancer genome sequencing data","volume":"23","year":"2022","journal-title":"Nat Rev Genet"},{"key":"2026092500100928000_2026.09.14.751548v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgw055"},{"key":"2026092500100928000_2026.09.14.751548v1.3","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev-biodatasci-122320-120920","article-title":"Mutational Signatures: From Methods to Mechanisms","volume":"4","year":"2021","journal-title":"Annu Rev Biomed Data Sci"},{"key":"2026092500100928000_2026.09.14.751548v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00377-7"},{"key":"2026092500100928000_2026.09.14.751548v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.12.008"},{"key":"2026092500100928000_2026.09.14.751548v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.04.024"},{"key":"2026092500100928000_2026.09.14.751548v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2021.08.007"},{"key":"2026092500100928000_2026.09.14.751548v1.8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0221235"},{"key":"2026092500100928000_2026.09.14.751548v1.9","doi-asserted-by":"crossref","unstructured":"Islam, S. 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