{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T20:01:19Z","timestamp":1781121679132,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,7]]},"group-title":"Bioinformatics","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T00:00:00Z","timestamp":1780790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institutes of Health of the United States","award":["R01LM013438"],"award-info":[{"award-number":["R01LM013438"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Germline variation shapes cancer risk, yet its influence on the evolutionary dynamics of established tumors remains poorly understood. In multiple myeloma, subclonal diversification drives disease progression and treatment failure, but the heritable factors that modulate this process are unknown.<\/jats:p>\n                <jats:p>\n                  Here, we show that germline variation is associated with tumor evolutionary features, implicating inherited regulation in subclonal expansion. Integrating germline variation with tumor evolutionary parameters identifies variants associated with evolutionary features, with signals enriched in regulatory regions, consistent with a transcriptional basis. We further identify\n                  <jats:italic>TBKBP1<\/jats:italic>\n                  as a key locus linking germline variation to tumor evolution and clinical outcome.\n                <\/jats:p>\n                <jats:p>\n                  Germline variation at this locus is associated with\n                  <jats:italic>TBKBP1<\/jats:italic>\n                  expression and subclonal expansion, and\n                  <jats:italic>TBKBP1<\/jats:italic>\n                  expression correlates with adverse prognosis, consistent across independent cohorts. Functional analyses demonstrate that\n                  <jats:italic>TBKBP1<\/jats:italic>\n                  promotes proliferation and activates MYC, mTORC1 and non-canonical NF-\u03baB signaling pathway.\n                <\/jats:p>\n                <jats:p>\n                  Together, these findings establish germline regulatory variation as a determinant of tumor evolutionary dynamics and identify\n                  <jats:italic>TBKBP1<\/jats:italic>\n                  as a mediator linking inherited variation to subclonal expansion and disease progression in multiple myeloma.\n                <\/jats:p>","DOI":"10.64898\/2026.06.05.730550","type":"posted-content","created":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T10:40:14Z","timestamp":1780828814000},"source":"Crossref","is-referenced-by-count":0,"title":["Germline regulation of tumor evolutionary dynamics shapes multiple myeloma progression"],"prefix":"10.64898","author":[{"given":"Hai","family":"Chen","sequence":"first","affiliation":[{"name":"College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA"},{"name":"Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA"},{"name":"Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingmin","family":"Shu","sequence":"additional","affiliation":[{"name":"College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA"},{"name":"Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rekha","family":"Mudappathi","sequence":"additional","affiliation":[{"name":"College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA"},{"name":"Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA"},{"name":"Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, AZ 85259, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Arizona, Scottsdale, 85259, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leif","family":"Bergsagel","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Scottsdale, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, AZ 85259, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifu","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changxin","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4002-7497","authenticated-orcid":false,"given":"Li","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA"},{"name":"Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061012201044000_2026.06.05.730550v1.1","doi-asserted-by":"crossref","unstructured":"Mubin, N. , Alnukhali, M. , Ahmad, N. , Driscoll, J. J. & Ahmad, A. Multidimensional tumor heterogeneity and its role in therapeutic resistance. Front. Immunol. 17, 1794130.","DOI":"10.3389\/fimmu.2026.1794130"},{"key":"2026061012201044000_2026.06.05.730550v1.2","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1016\/j.cell.2026.03.025","article-title":"Mapping intratumor heterogeneity across layers for advancing immunotherapy","volume":"189","year":"2026","journal-title":"Cell"},{"key":"2026061012201044000_2026.06.05.730550v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00734-2"},{"key":"2026061012201044000_2026.06.05.730550v1.4","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.tig.2019.04.005","article-title":"Germline variants impact on somatic events during tumorigenesis","volume":"35","year":"2019","journal-title":"Trends Genet. TIG"},{"key":"2026061012201044000_2026.06.05.730550v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2020.10.005"},{"key":"2026061012201044000_2026.06.05.730550v1.6","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-1045"},{"key":"2026061012201044000_2026.06.05.730550v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4156"},{"key":"2026061012201044000_2026.06.05.730550v1.8","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1002\/ijc.31351","article-title":"Interaction analysis between germline susceptibility loci and somatic alterations in lung cancer","volume":"143","year":"2018","journal-title":"Int. J. Cancer"},{"key":"2026061012201044000_2026.06.05.730550v1.9","doi-asserted-by":"crossref","first-page":"102248","DOI":"10.1016\/j.isci.2021.102248","article-title":"Germline variants predictive of tumor mutational burden and immune checkpoint inhibitor efficacy","volume":"24","year":"2021","journal-title":"iScience"},{"key":"2026061012201044000_2026.06.05.730550v1.10","doi-asserted-by":"crossref","first-page":"btag127","DOI":"10.1093\/bioinformatics\/btag127","article-title":"Competing subclones and fitness diversity shape tumor evolution across cancer types","volume":"42","year":"2026","journal-title":"Bioinformatics"},{"key":"2026061012201044000_2026.06.05.730550v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01853-0"},{"key":"2026061012201044000_2026.06.05.730550v1.12","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1078"},{"key":"2026061012201044000_2026.06.05.730550v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653"},{"key":"2026061012201044000_2026.06.05.730550v1.14","doi-asserted-by":"publisher","DOI":"10.1037\/a0031034"},{"key":"2026061012201044000_2026.06.05.730550v1.15","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan2507"},{"key":"2026061012201044000_2026.06.05.730550v1.16","first-page":"105495","article-title":"The Human Pathology Atlas for deciphering the prognostic features of human cancers","volume":"111","year":"2024","journal-title":"eBioMedicine"},{"key":"2026061012201044000_2026.06.05.730550v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1086"},{"key":"2026061012201044000_2026.06.05.730550v1.18","doi-asserted-by":"crossref","first-page":"R5","DOI":"10.1186\/bcr2468","article-title":"Effect of training-sample size and classification difficulty on the accuracy of genomic predictors","volume":"12","year":"2010","journal-title":"Breast Cancer Res. BCR"},{"key":"2026061012201044000_2026.06.05.730550v1.19","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2013.087809"},{"key":"2026061012201044000_2026.06.05.730550v1.20","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-4046"},{"key":"2026061012201044000_2026.06.05.730550v1.21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008786"},{"key":"2026061012201044000_2026.06.05.730550v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-024-01020-z"},{"key":"2026061012201044000_2026.06.05.730550v1.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"2026061012201044000_2026.06.05.730550v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/ng1180"},{"key":"2026061012201044000_2026.06.05.730550v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.02.004"},{"key":"2026061012201044000_2026.06.05.730550v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.003"},{"key":"2026061012201044000_2026.06.05.730550v1.27","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201110131"},{"key":"2026061012201044000_2026.06.05.730550v1.28","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1016\/j.semcancer.2022.09.007","article-title":"Tumor glycolysis, an essential sweet tooth of tumor cells","volume":"86","year":"2022","journal-title":"Semin. Cancer Biol"},{"key":"2026061012201044000_2026.06.05.730550v1.29","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1158\/1078-0432.CCR-17-3070","article-title":"Oxidative Phosphorylation as an Emerging Target in Cancer Therapy","volume":"24","year":"2018","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res"},{"key":"2026061012201044000_2026.06.05.730550v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2007.07.003"},{"key":"2026061012201044000_2026.06.05.730550v1.31","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae973"},{"key":"2026061012201044000_2026.06.05.730550v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0429-8"},{"key":"2026061012201044000_2026.06.05.730550v1.33","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1016\/j.chembiol.2025.07.004","article-title":"Targeting the MYC oncogene with a selective bi-steric mTORC1 inhibitor elicits tumor regression in MYC-driven cancers","volume":"32","year":"2025","journal-title":"Cell Chem. Biol"},{"key":"2026061012201044000_2026.06.05.730550v1.34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.exphem.2017.02.004","article-title":"Role of mTORC1-S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemia","volume":"50","year":"2017","journal-title":"Exp. Hematol"},{"key":"2026061012201044000_2026.06.05.730550v1.35","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018016733"},{"key":"2026061012201044000_2026.06.05.730550v1.36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023971"},{"key":"2026061012201044000_2026.06.05.730550v1.37","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1038\/s41594-024-01338-y","article-title":"Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD","volume":"31","year":"2024","journal-title":"Nat. Struct. Mol. Biol"},{"key":"2026061012201044000_2026.06.05.730550v1.38","doi-asserted-by":"publisher","DOI":"10.1101\/gad.962902"},{"key":"2026061012201044000_2026.06.05.730550v1.39","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41392-020-00312-6","article-title":"Targeting NF-\u03baB pathway for the therapy of diseases: mechanism and clinical study","volume":"5","year":"2020","journal-title":"Signal Transduct. Target. Ther"},{"key":"2026061012201044000_2026.06.05.730550v1.40","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1038\/s41467-024-46728-4","article-title":"Aberrant non-canonical NF-\u03baB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma","volume":"15","year":"2024","journal-title":"Nat. Commun"},{"key":"2026061012201044000_2026.06.05.730550v1.41","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/s41586-025-09374-4","article-title":"Fluctuating DNA methylation tracks cancer evolution at clinical scale","volume":"645","year":"2025","journal-title":"Nature"},{"key":"2026061012201044000_2026.06.05.730550v1.42","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1007\/978-3-030-50420-5_42","article-title":"MMRF-CoMMpass Data Integration and Analysis for Identifying Prognostic Markers","volume":"12139","year":"2020","journal-title":"Comput. Sci. \u2013 ICCS 2020"},{"key":"2026061012201044000_2026.06.05.730550v1.43","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"2026061012201044000_2026.06.05.730550v1.44","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.21037\/atm-21-4227","article-title":"Estimating tumor mutational burden across multiple cancer types using whole-exome sequencing","volume":"9","year":"2021","journal-title":"Ann. Transl. Med"},{"key":"2026061012201044000_2026.06.05.730550v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2011.457"},{"key":"2026061012201044000_2026.06.05.730550v1.46","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaa927"},{"key":"2026061012201044000_2026.06.05.730550v1.47","doi-asserted-by":"publisher","DOI":"10.1002\/mpr.1608"},{"key":"2026061012201044000_2026.06.05.730550v1.48","unstructured":"Andrew Futreal, H. Introduction to Mediation, Moderation, and Conditional Process Analysis: Third Edition: A Regression-Based Approach. Guilford Press https:\/\/www.guilford.com\/books\/Introduction-to-Mediation-Moderation-and-Conditional-Process-Analysis\/Andrew-Hayes\/9781462549030?srsltid=AfmBOorK2AQg-qHR0BnPl9tPtmJBfT4nxprThcVBS_DajkSPREuziV81 (2018)."},{"key":"2026061012201044000_2026.06.05.730550v1.49","doi-asserted-by":"publisher","DOI":"10.1086\/651257"},{"key":"2026061012201044000_2026.06.05.730550v1.50","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAF1250"},{"key":"2026061012201044000_2026.06.05.730550v1.51","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-17-0130"},{"key":"2026061012201044000_2026.06.05.730550v1.52","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/24.4.596"},{"key":"2026061012201044000_2026.06.05.730550v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(73)90341-3"},{"key":"2026061012201044000_2026.06.05.730550v1.54","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2026061012201044000_2026.06.05.730550v1.55","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"2026061012201044000_2026.06.05.730550v1.56","doi-asserted-by":"crossref","unstructured":"Mi, L. , W, H. & S, A. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, (2014).","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026061012201044000_2026.06.05.730550v1.57","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm087"},{"key":"2026061012201044000_2026.06.05.730550v1.58","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","year":"2015","journal-title":"Cell Syst"},{"key":"2026061012201044000_2026.06.05.730550v1.59","doi-asserted-by":"publisher","DOI":"10.1101\/060012"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.05.730550","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T19:20:24Z","timestamp":1781119224000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.05.730550"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,7]]},"references-count":59,"URL":"https:\/\/doi.org\/10.64898\/2026.06.05.730550","relation":{},"subject":[],"published":{"date-parts":[[2026,6,7]]},"subtype":"preprint"}}