DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution
Aberrant DNA methylation has been described in nearly all human cancers, yet its interplay with genomic alterations during tumor evolution is poorly understood. To explore this, we performed reduced representation bisulfite sequencing on 217 tumor and matched normal regions from 59 patients with non-small cell lung cancer from the TRACERx study to deconvolve tumor methylation. We developed two metrics for integrative evolutionary analysis with DNA and RNA sequencing data. Intratumoral methylation distance quantifies intratumor DNA methylation heterogeneity. M<sub>R</sub>/M<sub>N</sub> classifies genes based on the rate of hypermethylation at regulatory (M<sub>R</sub>) versus nonregulatory (M<sub>N</sub>) CpGs to identify driver genes exhibiting recurrent functional hypermethylation. We identified DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes. We propose two complementary mechanisms that converge for copy number alteration-affected chromatin to undergo the epigenetic equivalent of an allosteric activity transition. Hypermethylated driver genes under positive selection may open avenues for therapeutic stratification of patients.
Authors
- Hugo J.W.L. Aerts (ORCID: https://orcid.org/0000-0002-2122-2003)
- Cristina Naceur‐Lombardelli (ORCID: https://orcid.org/0000-0002-7097-0307)
- Teresa Marafioti (ORCID: https://orcid.org/0000-0003-1223-6275)
- Clare E. Weeden (ORCID: https://orcid.org/0000-0002-1561-1416)
- Jack Davies Hodgkinson
- Paulo De Sousa (ORCID: https://orcid.org/0000-0003-3011-4116)
- Reena Khiroya
- Tamara Denner
- Claudia Lee (ORCID: https://orcid.org/0000-0003-1715-2265)
- Xiaoxi Pan (ORCID: https://orcid.org/0000-0002-6146-5771)
- Seng Kuong Anakin Ung (ORCID: https://orcid.org/0009-0007-7231-0461)
- Mickael Escudero (ORCID: https://orcid.org/0000-0002-1336-815X)
- Pratibha Shah
- Richard Stone (ORCID: https://orcid.org/0000-0001-8059-3800)
- Gary Royle (ORCID: https://orcid.org/0000-0002-8548-7684)
- Corentin Richard (ORCID: https://orcid.org/0000-0001-9732-0219)
- Robert Stephens (ORCID: https://orcid.org/0000-0002-7510-1143)
- Yinyin Yuan (ORCID: https://orcid.org/0000-0002-8556-4707)
- Sergio A. Quezada (ORCID: https://orcid.org/0000-0002-9763-1700)
- Aiman Alzetani (ORCID: https://orcid.org/0000-0002-3373-6714)
- David Lawrence (ORCID: https://orcid.org/0000-0003-0502-0847)
- William Hill (ORCID: https://orcid.org/0000-0002-9591-1389)
- Pawan Dhami (ORCID: https://orcid.org/0000-0002-5408-1833)
- Babu Naidu
- Jayant K. Rane (ORCID: https://orcid.org/0000-0002-9594-3938)
- Simone Zaccaria (ORCID: https://orcid.org/0000-0002-5265-7392)
- Wei-Ting Lu (ORCID: https://orcid.org/0000-0002-1405-4806)
- Nikos Kostoulas
- Roberto Salgado (ORCID: https://orcid.org/0000-0002-1110-3801)
- Neal Navani (ORCID: https://orcid.org/0000-0002-6412-7516)
- Charles Swanton (ORCID: https://orcid.org/0000-0002-4299-3018)
- Hilgardt Raubenheimer
- Takahiro Karasaki (ORCID: https://orcid.org/0000-0001-6863-2360)
- Maria Litovchenko (ORCID: https://orcid.org/0000-0003-1868-4933)
- Stephan Beck (ORCID: https://orcid.org/0000-0001-5290-2151)
- Ekaterini Boleti
- Andrew J. Atkin (ORCID: https://orcid.org/0000-0002-3819-3448)
- Yutaka Naito (ORCID: https://orcid.org/0000-0001-6827-601X)
- Camilla Pilotti
- Rachel Scott (ORCID: https://orcid.org/0000-0001-5847-3378)
- Colin R. Lindsay (ORCID: https://orcid.org/0000-0001-8167-5461)
- Wing Kin Liu
- Allan Hackshaw (ORCID: https://orcid.org/0000-0002-5570-5070)
- Alexander James Procter
- Paulina Prymas
- Katey S.S. Enfield (ORCID: https://orcid.org/0000-0002-4551-6073)
- James R. Black (ORCID: https://orcid.org/0000-0001-5598-7752)
- Sophia Ward (ORCID: https://orcid.org/0000-0002-4273-9810)
- Jonas Demeulemeester (ORCID: https://orcid.org/0000-0002-2660-2478)
- Rebecca Boyles (ORCID: https://orcid.org/0000-0003-0073-6854)
- Zoltán Szállási (ORCID: https://orcid.org/0000-0001-5395-7509)
- Nikki Totton (ORCID: https://orcid.org/0000-0002-1900-2773)
- Olivia Lucas (ORCID: https://orcid.org/0000-0001-8169-7767)
- Alexandra Rice (ORCID: https://orcid.org/0000-0002-0527-7960)
- Anshuman Chaturvedi (ORCID: https://orcid.org/0000-0003-1575-1176)
- Oriol Pich (ORCID: https://orcid.org/0000-0002-1956-1882)
- Jeanette Kittel (ORCID: https://orcid.org/0000-0002-8964-4640)
- Gareth A. Wilson (ORCID: https://orcid.org/0000-0002-5703-9710)
- Vittorio Barbè
- Catarina Veiga (ORCID: https://orcid.org/0000-0002-4132-2554)
- Jacki Goldman (ORCID: https://orcid.org/0000-0002-2981-5022)
- Maise Al Bakir (ORCID: https://orcid.org/0000-0002-0846-8332)
- David R. Pearce (ORCID: https://orcid.org/0000-0001-8443-2924)
- Kwang Cheol Koh (ORCID: https://orcid.org/0000-0002-9146-450X)
- Elaine Borg (ORCID: https://orcid.org/0000-0001-5930-2239)
- Mairead MacKenzie
- Özgen Deniz (ORCID: https://orcid.org/0000-0001-7268-1923)
- Jérôme Nicod (ORCID: https://orcid.org/0000-0003-2459-3480)
- Andrew Kidd (ORCID: https://orcid.org/0000-0003-1691-4395)
- Lily Robinson
- Roberto Vendramin (ORCID: https://orcid.org/0000-0001-7191-4887)
- Hanyun Zhang (ORCID: https://orcid.org/0000-0002-4140-7881)
- Sarah Benafif (ORCID: https://orcid.org/0000-0003-1407-1697)
- Emma Nye (ORCID: https://orcid.org/0000-0001-9154-3526)
- Sonya Hessey (ORCID: https://orcid.org/0000-0001-9856-424X)
- Crispin T. Hiley (ORCID: https://orcid.org/0000-0002-5869-0775)
- Alexander M. Frankell (ORCID: https://orcid.org/0000-0002-0341-7878)
- Krupa Thakkar
- Abigail Bunkum (ORCID: https://orcid.org/0000-0002-7753-9421)
- Anca Grapa
- Apostolos Nakas (ORCID: https://orcid.org/0000-0001-6993-1514)
- Yien Ning Sophia Wong (ORCID: https://orcid.org/0000-0003-1903-6110)
- Francesco Fraioli (ORCID: https://orcid.org/0000-0003-0821-6327)
- James M. Wilson (ORCID: https://orcid.org/0000-0003-2444-9171)
- Gary Middleton (ORCID: https://orcid.org/0000-0001-5695-3474)
- C. Donovan Bailey (ORCID: https://orcid.org/0000-0002-3123-4083)
- Benny Chain (ORCID: https://orcid.org/0000-0002-7417-3970)
- Heather Cheyne
- Mary Falzon (ORCID: https://orcid.org/0009-0006-6210-4376)
- Caroline Dive (ORCID: https://orcid.org/0000-0002-1726-8850)
- Felice Granato
- Miljana Tanić (ORCID: https://orcid.org/0000-0003-3102-776X)
- Victoria J. Spanswick
- Amrita Bajaj (ORCID: https://orcid.org/0000-0002-9251-2753)
- Michelle Leung (ORCID: https://orcid.org/0000-0001-9555-1080)
- Miklós Dióssy (ORCID: https://orcid.org/0000-0003-0308-6615)
- Robert E. Hynds (ORCID: https://orcid.org/0000-0002-2170-8791)
- Maria Zagorulya (ORCID: https://orcid.org/0000-0002-4478-5378)
- Emma Colliver (ORCID: https://orcid.org/0000-0002-1497-0740)
- David A. Moore (ORCID: https://orcid.org/0000-0001-9116-346X)
- Khalid AbdulJabbar (ORCID: https://orcid.org/0000-0002-4411-4435)
- Jonathan Steif (ORCID: https://orcid.org/0000-0003-2883-1239)
- Philip Hobson (ORCID: https://orcid.org/0000-0001-5117-2994)
- Clare Puttick (ORCID: https://orcid.org/0009-0006-3022-8737)
- Supreet Kaur Bola (ORCID: https://orcid.org/0000-0001-8558-8197)
- Jonathan Tugwood
- Sridhar Rathinam (ORCID: https://orcid.org/0000-0002-1065-0045)
- Rachel Rosenthal (ORCID: https://orcid.org/0000-0002-0900-8709)
- Leah Ensell
- Tom L. Kaufmann (ORCID: https://orcid.org/0000-0003-4374-1338)
- Georgia Stavrou (ORCID: https://orcid.org/0000-0002-8427-5233)
- Thomas B.K. Watkins (ORCID: https://orcid.org/0000-0001-7414-737X)
- Yin Wu (ORCID: https://orcid.org/0000-0003-4080-3935)
- Nana Mensah (ORCID: https://orcid.org/0000-0003-0832-2816)
- Dhruva Biswas (ORCID: https://orcid.org/0000-0001-9141-5188)
- Mihaela Angelova (ORCID: https://orcid.org/0000-0002-0495-9695)
- Yvonne Summers
- Mariam Jamal‐Hanjani (ORCID: https://orcid.org/0000-0003-1212-1259)
- Rija Zaidi (ORCID: https://orcid.org/0000-0002-2259-4319)
- Gerald Langman
- Eva Grönroos (ORCID: https://orcid.org/0000-0001-8303-5409)
- Dionysis Papadatos-Pastos
- Lucrezia Patruno (ORCID: https://orcid.org/0000-0002-3721-9984)
- Zoe Ramsden
- Ieva Usaite (ORCID: https://orcid.org/0000-0001-6154-0447)
- Sara Waplington
- Angeliki Karamani
- Kerstin Thol (ORCID: https://orcid.org/0000-0002-4624-118X)
- Andrew Feber (ORCID: https://orcid.org/0000-0001-5282-0498)
- Siqi Lai (ORCID: https://orcid.org/0000-0002-3845-1961)
- Selvaraju Veeriah (ORCID: https://orcid.org/0000-0002-1217-0387)
- Andrew Rowan (ORCID: https://orcid.org/0000-0003-1926-9707)
- Allan D. Kirk (ORCID: https://orcid.org/0000-0003-2004-5962)
- Nicholas McGranahan (ORCID: https://orcid.org/0000-0001-9537-4045)
- Mpho Malima
- John Le Quesne (ORCID: https://orcid.org/0000-0003-3552-7446)
- George Kassiotis (ORCID: https://orcid.org/0000-0002-8457-2633)
- Michael Shackcloth (ORCID: https://orcid.org/0000-0002-6494-9907)
- Ricky M. Thakrar (ORCID: https://orcid.org/0000-0001-9793-2223)
- Kristiana Grigoriadis (ORCID: https://orcid.org/0000-0002-8435-0176)
- Aya Osman (ORCID: https://orcid.org/0000-0002-2048-5039)
- Angela Leek
- Despoina Karagianni (ORCID: https://orcid.org/0000-0002-8605-5808)
- Daniele Marinelli (ORCID: https://orcid.org/0000-0002-6002-363X)
- Dean A. Fennell
- Sean Dulloo
- Fleur Monk
- Mathew Thomas (ORCID: https://orcid.org/0000-0002-2374-0146)
- Nnennaya Kanu (ORCID: https://orcid.org/0000-0001-7232-1952)
- Antonia Toncheva
- Davide Patrini (ORCID: https://orcid.org/0000-0002-2492-799X)
- Madava Djearaman
- Samuel Gamble
- Sadegh Saghafinia (ORCID: https://orcid.org/0000-0001-5695-9825)
- Carlos Martínez‐Ruiz (ORCID: https://orcid.org/0000-0002-4817-0565)
- Juliette Novasio
- Maria Chiara Pisciella
- Elizabeth Keene
- Serena Chee (ORCID: https://orcid.org/0000-0001-7244-9876)
- Sam M. Janes (ORCID: https://orcid.org/0000-0002-6634-5939)
- Gurdeep Matharu
- Nadia J. Fernandes (ORCID: https://orcid.org/0000-0003-4595-9939)
- Francisco Gimeno-Valiente (ORCID: https://orcid.org/0000-0003-0544-9459)
- Sean Smith (ORCID: https://orcid.org/0000-0001-6758-4037)
- Jacqui Shaw (ORCID: https://orcid.org/0000-0003-4227-503X)
- Emilie Martinoni Hoogenboom
- António Paiva‐Correia (ORCID: https://orcid.org/0000-0001-8725-0202)
- Helen L. Lowe (ORCID: https://orcid.org/0000-0001-8630-378X)
- Angela Dwornik
- Junaid Choudhary
- Mathew Carter
- John Hartley (ORCID: https://orcid.org/0000-0001-5987-8190)
- Roland F. Schwarz (ORCID: https://orcid.org/0000-0001-9155-4268)
- Akshay Jatin Patel (ORCID: https://orcid.org/0000-0001-9170-8618)
- Michelle Dietzen (ORCID: https://orcid.org/0000-0002-6853-7563)
- Molly Scotland
- Sarah Danson (ORCID: https://orcid.org/0000-0002-3593-2890)
- Sofina Begum (ORCID: https://orcid.org/0000-0001-7689-0087)
- Pat Gorman
- Philip Crosbie
- Mohamad Tufail
- Gillian Price
- J.F. Lester (ORCID: https://orcid.org/0000-0002-2311-070X)
- Harshil Bhayani
- Carla Castignani (ORCID: https://orcid.org/0000-0001-8689-9659)
- Silviu Buderi
- James W. Holding
- Ariana Huebner
- Kayalvizhi Selvaraju
- Rachel Leslie
- Stefan Boeing (ORCID: https://orcid.org/0000-0003-0495-5659)
- Rocco Bilancia
- Arjun Nair (ORCID: https://orcid.org/0000-0001-9270-3771)
- Erik Sahai (ORCID: https://orcid.org/0000-0002-3932-5086)
- Kendadai Rammohan
- Elizabeth Larose Cadieux (ORCID: https://orcid.org/0000-0002-9320-8040)
- Zoltán Káplár
- Peter Van Loo (ORCID: https://orcid.org/0000-0003-0292-1949)
- Azmina Sodha-Ramdeen
- Martin Förster (ORCID: https://orcid.org/0000-0003-3876-7269)
- Imran Noorani (ORCID: https://orcid.org/0000-0003-4289-2345)
- Vijay Joshi (ORCID: https://orcid.org/0000-0001-6803-4379)
- Nicolai J. Birkbak (ORCID: https://orcid.org/0000-0003-1613-9587)
- Matthew Krebs (ORCID: https://orcid.org/0000-0001-7540-3064)
- Kerstin Haase (ORCID: https://orcid.org/0000-0002-0944-5618)
- Eric Lim (ORCID: https://orcid.org/0000-0002-9078-3226)
- Tracey Cruickshank
- Sharon Vanloo
- Cian Murphy
- Bashair M. Mussa (ORCID: https://orcid.org/0000-0002-1554-6319)
- Olga Chervova (ORCID: https://orcid.org/0000-0002-1671-9488)
- Shirley Richardson
- Chiara Proli
- Kunal Bhakhri
- Amy S. Walker (ORCID: https://orcid.org/0000-0003-0140-0586)
- Madeleine Hewish
- Paul Ashford (ORCID: https://orcid.org/0000-0003-4079-0257)
- Daniel Kaniu
- Charles‐Antoine Collins‐Fekete (ORCID: https://orcid.org/0000-0003-2464-8795)
- Fiona Helen Blackhall (ORCID: https://orcid.org/0000-0001-8716-3395)
- James L. Reading (ORCID: https://orcid.org/0000-0001-5381-978X)
- Jennifer Whiteley
- Helen Shackleford
- Heli Vaikkinen
- Gerasimos-Theodoros Mastrokalos
- Zhihui Zhang (ORCID: https://orcid.org/0000-0002-8183-1054)
- Pedro Oliveira (ORCID: https://orcid.org/0000-0001-8912-2490)
- Mohammed S. Khalil (ORCID: https://orcid.org/0000-0002-1539-5629)
- Judith Cave (ORCID: https://orcid.org/0000-0002-1497-0310)
- Kezhong Chen (ORCID: https://orcid.org/0000-0002-9723-6153)
- Claire Wilson (ORCID: https://orcid.org/0000-0002-6401-2014)
- Piotr Pawlik (ORCID: https://orcid.org/0009-0008-7075-615X)
- Andrew G. Nicholson
- Mo Asif
- Asia Ahmed
- Jack French
- Katherine D. Brown
- Siow Ming Lee
- Anne-Marie Hacker
- Eustace Fontaine
- Martin Hirst
- Kevin G. Blyth
- Thomas Peter Jones (ORCID: https://orcid.org/0000-0001-5706-7255)
- Robert Bentham
- Simon Jordan
- Tanya Ahmad
- Anand Devaraj
- Monica Sivakumar
- Mandeesh Sangha
- Magali N. Taylor
- S. Harries
- Kayleigh Gilbert
- Craig Dick
- Steve Bandula
- Mansi Shah
- Hema Chavan
- Petra Georg
- Karl S. Peggs
- Lyn Ambrose
- Peter Russell
- Emilia L. Lim (ORCID: https://orcid.org/0009-0009-2954-1795)
- Keith M. Kerr
- Sarah Booth
- Leena Dennis Joseph (ORCID: https://orcid.org/0000-0002-9395-2961)
- David Chuter
- Xiaohong Liu
- Michalina Magala
Institutions
- Semmelweis University (HU)
- Eötvös Loránd University (HU)
- Medigene (Germany) (DE)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- University College Hospital (GB)
- Swansea Bay University Health Board (GB)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Garvan Institute of Medical Research (AU)
- University of British Columbia (CA)
- Institute of Cancer Research (GB)
- University of Liverpool (GB)
- University of Leicester (GB)
- Queen Mary University of London (GB)
- Royal Free London NHS Foundation Trust (GB)
- University of Cologne (DE)
- University of Aberdeen (GB)
- Guy's and St Thomas' NHS Foundation Trust (GB)
- Peking University (CN)
- Aarhus University (DK)
- Max Delbrück Center (DE)
- NHS Greater Glasgow and Clyde (GB)
- Singleton Hospital (GB)
- Peter MacCallum Cancer Centre (AU)
- Aberdeen Royal Infirmary (GB)
- Princess Alexandra Hospital NHS Trust (GB)
- The Francis Crick Institute (GB)
- Royal London Hospital (GB)
- Cancer Research UK (GB)
- Buda Health Center (HU)
- Golden Jubilee National Hospital (GB)
- Aarhus University Hospital (DK)
- University Hospitals of Leicester NHS Trust (GB)
- Whittington Hospital (GB)
- Harefield Hospital (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- University of Surrey (GB)
- University of Manchester (GB)
- Maastricht University (NL)
- Liverpool Heart and Chest Hospital (GB)
- London Cancer (GB)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Manchester University NHS Foundation Trust (GB)
- NHS Grampian (GB)
- Sheffield Teaching Hospitals NHS Foundation Trust (GB)
- Oncology Institute of Vojvodina (RS)
- Dana-Farber Cancer Institute (US)
- NIHR Southampton Biomedical Research Centre (GB)
- Royal Marsden Hospital (GB)
- Peking University People's Hospital (CN)
- Cancer Research UK Manchester Institute (GB)
- Canada's Michael Smith Genome Sciences Centre (CA)
- The Christie NHS Foundation Trust (GB)
- National Cancer Centre Singapore (SG)
- Cancer Research UK Scotland Institute (GB)
- Genomics England (GB)
- Immune Regulation (United Kingdom) (GB)
- Royal Surrey NHS Foundation Trust (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- Danish Cancer Society (DK)
- Wythenshawe Hospital (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- Genomics (United Kingdom) (GB)
- University Hospital Cologne (DE)
- Institute of Structural and Molecular Biology (GB)
- Queen Elizabeth University Hospital (GB)
- Dana-Farber Brigham Cancer Center (US)
- The Patients Association (GB)
- Cancer Research UK Manchester Centre
- Berlin Institute for the Foundations of Learning and Data (DE)
- University College London (GB)
- Imperial College London (GB)
- Mass General Brigham (US)
- University of Glasgow (GB)
- University of Birmingham (GB)
- Sapienza University of Rome (IT)
- Epigenomics (Germany) (DE)
- University of Sheffield (GB)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s41588-025-02307-x
- Citations
- 4
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 3.22