Quantifying cell divisions along evolutionary lineages in cancer

Quantifying cell divisions along evolutionary lineages in cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Quantifying cell divisions along evolutionary lineages in cancer Kamila Naxerova, Martin Blohmer, David Cheek, Wei-Ting Hung, Maria Kessler, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3839927/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Feb, 2025 Read the published version in Nature Genetics → Version 1 posted You are reading this latest preprint version Abstract Cell division drives somatic evolution but is challenging to quantify in human tissues. Here, we develop a framework to count cell divisions with DNA replication-related mutations in polyguanine homopolymers. We apply the method in two different scenarios. First, analyzing 505 samples from 37 patients, we study the milestones of colorectal cancer evolution. We find that tumor founder cells divide at similar rates as normal intestinal stem cells over a patient’s lifetime. Primary tumors diversify at ~250 divisions from the founder cell, while distant metastasis divergence occurs significantly later, at ~500 divisions. Notably, distant but not lymph node metastases share a common origin with primary tumor regions that have undergone surplus divisions, tying subclonal expansion to metastatic capacity. Second, we analyze a cohort of 73 multifocal lung cancers with ambiguous origins. We show that the cell division burden of the tumors’ common ancestor distinguishes independent primary tumors from intrapulmonary metastases and correlates with patient survival. Metastatic capacity is tied to more extensive proliferation, mirroring our results in colorectal cancer. The cell division history of human cancers contains valuable biological and clinical information and can be effectively interrogated with our simple framework. Biological sciences/Genetics Biological sciences/Cancer/Gastrointestinal cancer Biological sciences/Cancer/Lung cancer Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryDocument.pdf Supplementarytables.xlsx Cite Share Download PDF Status: Published Journal Publication published 04 Feb, 2025 Read the published version in Nature Genetics → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3839927","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":266509151,"identity":"f92e1d04-8918-4ab6-9aa5-bdd84acc557f","order_by":0,"name":"Kamila Naxerova","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-7744-5110","institution":"Harvard Medical School","correspondingAuthor":true,"prefix":"","firstName":"Kamila","middleName":"","lastName":"Naxerova","suffix":""},{"id":266509152,"identity":"e533c625-fd9b-4044-89d2-b876479fa868","order_by":1,"name":"Martin Blohmer","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Blohmer","suffix":""},{"id":266509153,"identity":"50cf934c-7275-4888-8d68-97057f460c47","order_by":2,"name":"David Cheek","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Cheek","suffix":""},{"id":266509154,"identity":"e00e55f3-dfec-4da2-bed2-47125aa7aca3","order_by":3,"name":"Wei-Ting Hung","email":"","orcid":"","institution":"National Taiwan University","correspondingAuthor":false,"prefix":"","firstName":"Wei-Ting","middleName":"","lastName":"Hung","suffix":""},{"id":266509155,"identity":"f37ae43e-6aa7-4394-9f13-e0f2cd60b8bc","order_by":4,"name":"Maria Kessler","email":"","orcid":"","institution":"Heidelberg University","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Kessler","suffix":""},{"id":266509156,"identity":"6fcf1fab-39ac-4e42-89c4-15b185bb281c","order_by":5,"name":"I-Hsiu Lee","email":"","orcid":"https://orcid.org/0000-0001-7200-7867","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"I-Hsiu","middleName":"","lastName":"Lee","suffix":""},{"id":266509157,"identity":"111b7184-3f74-4e61-8af5-86b82d3e4581","order_by":6,"name":"Alexander Gorelick","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Gorelick","suffix":""},{"id":266509158,"identity":"8ce017b5-318c-4ac8-a1f1-c8318e0fb5f5","order_by":7,"name":"Ching-Yeuh Yang","email":"","orcid":"https://orcid.org/0000-0003-2855-5756","institution":"Taipei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ching-Yeuh","middleName":"","lastName":"Yang","suffix":""},{"id":266509159,"identity":"e1e07155-5991-4f74-a1ae-b140acf81f62","order_by":8,"name":"Yi-Chen Yeh","email":"","orcid":"https://orcid.org/0000-0002-6442-4967","institution":"Taipai Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi-Chen","middleName":"","lastName":"Yeh","suffix":""},{"id":266509160,"identity":"fe8ffeb4-2770-48d4-a2d3-14cf22c45e14","order_by":9,"name":"Hsiang-Ling Ho","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hsiang-Ling","middleName":"","lastName":"Ho","suffix":""},{"id":266509161,"identity":"908e18e5-db6a-4686-b217-acf8bea1b37c","order_by":10,"name":"Dorothee Speiser","email":"","orcid":"","institution":"Charité - 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