Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Reactivated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695, a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

Advanced Technology Center for Aging Research IRCCS INRCA Ancona Italy

Ben May Department for Cancer Research The University of Chicago Chicago IL USA

Biobanco IBSP CV FISABIO Valencia Spain

Cancer Genomics Research Laboratory Leidos Biomedical Research Frederick National Laboratory for Cancer Research Frederick MD USA

Clinic of Laboratory and Precision Medicine IRCCS INRCA Ancona Italy

Department of Bioengineering University of California San Diego La Jolla CA USA

Department of Cancer Epidemiology and Primary Prevention Maria Skłodowska Curie National Research Institute of Oncology Warshaw Poland

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa FL USA

Department of Cellular and Molecular Medicine University of California San Diego La Jolla CA USA

Department of Clinical Epidemiology N N Blokhin National Medical Research Centre of Oncology Moscow Russia

Department of Clinical Sciences and Community Health University of Milan Milan Italy

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Łódź Poland

Department of Environmental Health Harvard T H Chan School of Public Health Boston MA USA

Department of Human Genetics The University of Chicago Chicago IL USA

Department of Mathematics Harvard University Cambridge MA USA

Department of Medicine Massachusetts General Hospital Boston MA USA

Department of Occupational Health and Toxicology National Center for Environmental Risk Monitoring National Institute of Public Health Bucharest Romania

Department of Oncology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Organismic and Evolutionary Biology Harvard University Cambridge MA USA

Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Department of Pathology Brigham and Women's Hospital Boston MA USA

Department of Pathology Centre Hospitalier de l'Université de Montréal Montreal Canada

Department of Pathology The University of Hong Kong Hong Kong China

Department of Pathology Yale School of Medicine New Haven CT USA

Department of Surgery Division of Thoracic Surgery Chung Shan Medical University Hospital Taichung Taiwan

Department of Thoracic Surgery Clinical Center of Serbia Belgrade Serbia

Digital Genomics Group Structural Biology Program Spanish National Cancer Research Center Madrid Spain

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Division of Pulmonary and Critical Care Medicine Mayo Clinic Rochester MN USA

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy

Genomic Epidemiology Branch International Agency for Research on Cancer Lyon France

IHU RespirERA Biobank BB 0033 0025 Côte d'Azur University Nice France

Institut universitaire de cardiologie et de pneumologie de Québec Laval University Quebec City Canada

Institute of Hygiene and Epidemiology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Medicine Chung Shan Medical University Taichung Taiwan

Institute of Population Health Sciences National Health Research Institutes Zhunan Taiwan

International Organisation for Cancer Prevention and Research Belgrade Serbia

Manchester Cancer Research Centre The University of Manchester Manchester UK

Manchester NIHR Biomedical Research Centre Manchester UK

Moores Cancer Center University of California San Diego La Jolla CA USA

Princess Margaret Cancer Center University of Toronto Toronto Ontario Canada

Queen Mary Hospital The University of Hong Kong Hong Kong China

Red Valenciana de Biobancos FISABIO Valencia Spain

Sanford Stem Cell Institute University of California San Diego La Jolla CA USA

Sylvester Comprehensive Cancer Center Department of Medicine University of Miami Miller School of Medicine Miami FL USA

The University of Chicago Medicine Comprehensive Cancer Center The University of Chicago Chicago IL USA

Thoracic Surgery Roswell Park Comprehensive Cancer Center Buffalo NY USA

Westat Rockville MD USA

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Cancer facts & figures 2023. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2023-cancer-facts-figures.html.

Yang P. et al. Adenocarcinoma of the Lung Is Strongly Associated with Cigarette Smoking: Further Evidence from a Prospective Study of Women. Am. J. Epidemiol. 156, 1114–1122 (2002). PubMed

Zappa C. & Mousa S. A. Non-small cell lung cancer: current treatment and future advances. Transl. Lung Cancer Res. 5, 288–300 (2016). PubMed PMC

Devarakonda S. et al. Genomic Profiling of Lung Adenocarcinoma in Never-Smokers. J. Clin. Orthod. 39, 3747–3758 (2021). PubMed PMC

Shi J. et al. Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population. Nat. Commun. 14, 1–17 (2023). PubMed PMC

Yachida S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010). PubMed PMC

Naxerova K. et al. Origins of lymphatic and distant metastases in human colorectal cancer. Science 357, 55–60 (2017). PubMed PMC

Reiter J. G. et al. Minimal functional driver gene heterogeneity among untreated metastases. Science 361, 1033–1037 (2018). PubMed PMC

Gerstung M. et al. The evolutionary history of 2,658 cancers. Nature 578, 122–128 (2020). PubMed PMC

Frankell A. M. et al. The evolution of lung cancer and impact of subclonal selection in TRACERx. Nature 616, 525–533 (2023). PubMed PMC

Jamal-Hanjani M. et al. Tracking the Evolution of Non–Small-Cell Lung Cancer. N. Engl. J. Med. 376, 2109–2121 (2017). PubMed

Hu X. et al. Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma. Nat. Commun. 10, 1–10 (2019). PubMed PMC

Al Bakir M. et al. The evolution of non-small cell lung cancer metastases in TRACERx. Nature 616, 534–542 (2023). PubMed PMC

Lee E. et al. Landscape of somatic retrotransposition in human cancers. Science 337, 967–971 (2012). PubMed PMC

Tubio J. M. C. et al. Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 345, 1251343 (2014). PubMed PMC

Burns K. H. Transposable elements in cancer. Nat. Rev. Cancer 17, 415–424 (2017). PubMed

Rodriguez-Martin B. et al. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nat. Genet. 52, 306–319 (2020). PubMed PMC

Burns K. H. Repetitive DNA in disease. Science 376, 353–354 (2022). PubMed

Zhang R. et al. LINE-1 retrotransposition promotes the development and progression of lung squamous cell carcinoma by disrupting the tumor-suppressor gene FGGY. Cancer Res. 79, 4453–4465 (2019). PubMed

Mendez-Dorantes C. & Burns K. H. LINE-1 retrotransposition and its deregulation in cancers: implications for therapeutic opportunities. Genes Dev. 37, 948–967 (2023). PubMed PMC

Mendez-Dorantes C. et al. Chromosomal rearrangements and instability caused by the LINE-1 retrotransposon. bioRxiv (2024) doi:10.1101/2024.12.14.628481. DOI

Rodić N. et al. Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. Nat. Med. 21, 1060–1064 (2015). PubMed PMC

Nguyen T. H. M. et al. L1 retrotransposon heterogeneity in ovarian tumor cell evolution. Cell Rep. 23, 3730–3740 (2018). PubMed

Zhang T. et al. Genomic and evolutionary classification of lung cancer in never smokers. Nat. Genet. 53, 1348–1359 (2021). PubMed PMC

Landi M. T. et al. Tracing Lung Cancer Risk Factors Through Mutational Signatures in Never-Smokers. Am. J. Epidemiol. 190, 962–976 (2021). PubMed PMC

Dentro S. C. et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 184, 2239–2254.e39 (2021). PubMed PMC

López S. et al. Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution. Nat. Genet. 52, 283–293 (2020). PubMed PMC

Zhu B. et al. The genomic and epigenomic evolutionary history of papillary renal cell carcinomas. Nat. Commun. 11, 3096 (2020). PubMed PMC

Alexandrov L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020). PubMed PMC

Thatikonda V. et al. Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers. Nat Cancer 4, 276–289 (2023). PubMed PMC

Spisak N., de Manuel M., Milligan W., Sella G. & Przeworski M. The clock-like accumulation of germline and somatic mutations can arise from the interplay of DNA damage and repair. PLoS Biol. 22, e3002678 (2024). PubMed PMC

Senkin S. et al. Geographic variation of mutagenic exposures in kidney cancer genomes. Nature 629, 910–918 (2024). PubMed PMC

Zhang T. et al. Genomic and evolutionary classification of lung cancer in never smokers. Nat. Genet. 53, 1348–1359 (2021). PubMed PMC

Fontana D. et al. Evolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients. Nat. Commun. 14, 5982 (2023). PubMed PMC

Haga Y. et al. Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma. Nat. Commun. 14, 8375 (2023). PubMed PMC

McGranahan N. et al. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci. Transl. Med. 7, 283ra54 (2015). PubMed PMC

Rosenthal R., McGranahan N., Herrero J., Taylor B. S. & Swanton C. DeconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution. Genome Biol. 17, 31 (2016). PubMed PMC

Degasperi A. et al. Substitution mutational signatures in whole-genome-sequenced cancers in the UK population. Science 376, (2022). PubMed PMC

Islam S. M. A. et al. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor. Cell Genom 2, None (2022). PubMed PMC

Rubanova Y. et al. Reconstructing evolutionary trajectories of mutation signature activities in cancer using TrackSig. Nat. Commun. 11, 1–12 (2020). PubMed PMC

Otlu B. et al. Topography of mutational signatures in human cancer. bioRxiv 2022.05.29.493921 (2023) doi:10.1101/2022.05.29.493921. PubMed DOI PMC

Stamatoyannopoulos J. A. et al. Human mutation rate associated with DNA replication timing. Nat. Genet. 41, 393–395 (2009). PubMed PMC

Whitfield M. L., George L. K., Grant G. D. & Perou C. M. Common markers of proliferation. Nat. Rev. Cancer 6, 99–106 (2006). PubMed

Negrini S., Gorgoulis V. G. & Halazonetis T. D. Genomic instability--an evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 11, 220–228 (2010). PubMed

Bhandari V., Li C. H., Bristow R. G., Boutros P. C. & PCAWG Consortium. Divergent mutational processes distinguish hypoxic and normoxic tumours. Nat. Commun. 11, 737 (2020). PubMed PMC

Höckel M., Schlenger K., Höckel S. & Vaupel P. Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res. 59, 4525–4528 (1999). PubMed

Emami Nejad A. et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int. 21, 62 (2021). PubMed PMC

Li T. et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 48, W509–W514 (2020). PubMed PMC

Liberzon A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739–1740 (2011). PubMed PMC

Liu N. et al. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature 553, 228–232 (2018). PubMed PMC

Li X. et al. LINE-1 transcription activates long-range gene expression. Nat. Genet. 56, 1494–1502 (2024). PubMed

Scott E. C. & Devine S. E. The Role of Somatic L1 Retrotransposition in Human Cancers. Viruses 9, (2017). PubMed PMC

Miglino N., Tamm M. & Borger P. Transposable element LINE1 is activated after exposure to cigarette smoke in primary human lung fibroblasts. Eur. Respir. J. 44, (2014).

Belgnaoui S. M., Gosden R. G., Semmes O. J. & Haoudi A. Human LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells. Cancer Cell Int. 6, 13 (2006). PubMed PMC

Gasior S. L., Wakeman T. P., Xu B. & Deininger P. L. The human LINE-1 retrotransposon creates DNA double-strand breaks. J. Mol. Biol. 357, 1383–1393 (2006). PubMed PMC

McKerrow W. et al. LINE-1 expression in cancer correlates with p53 mutation, copy number alteration, and S phase checkpoint. Proc. Natl. Acad. Sci. U. S. A. 119, (2022). PubMed PMC

Kazazian H. H. Jr & Moran J. V. Mobile DNA in Health and Disease. N. Engl. J. Med. 377, 361–370 (2017). PubMed PMC

Levin H. L. & Moran J. V. Dynamic interactions between transposable elements and their hosts. Nat. Rev. Genet. 12, 615–627 (2011). PubMed PMC

Morrish T. A. et al. DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nat. Genet. 31, 159–165 (2002). PubMed

Farkash E. A. & Luning Prak E. T. DNA damage and L1 retrotransposition. J. Biomed. Biotechnol. 2006, 37285 (2006). PubMed PMC

Mao Z., Bozzella M., Seluanov A. & Gorbunova V. DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells. Cell Cycle 7, 2902–2906 (2008). PubMed PMC

Suzuki J. et al. Genetic evidence that the non-homologous end-joining repair pathway is involved in LINE retrotransposition. PLoS Genet. 5, e1000461 (2009). PubMed PMC

Lieber M. R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem. 79, 181–211 (2010). PubMed PMC

Levin H. L. & Moran J. V. Dynamic interactions between transposable elements and their hosts. Nat. Rev. Genet. 12, 615–627 (2011). PubMed PMC

Rodgers K. & McVey M. Error-Prone Repair of DNA Double-Strand Breaks. J. Cell. Physiol. 231, 15–24 (2016). PubMed PMC

Doucet A. J., Wilusz J. E., Miyoshi T., Liu Y. & Moran J. V. A 3’ Poly(A) Tract Is Required for LINE-1 Retrotransposition. Mol. Cell 60, 728–741 (2015). PubMed PMC

Baldwin E. T. et al. Structures, functions and adaptations of the human LINE-1 ORF2 protein. Nature 626, 194–206 (2024). PubMed PMC

Wolff E. M. et al. Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer. PLoS Genet. 6, e1000917 (2010). PubMed PMC

Shademan M. et al. Promoter methylation, transcription, and retrotransposition of LINE-1 in colorectal adenomas and adenocarcinomas. Cancer Cell Int. 20, 1–16 (2020). PubMed PMC

Freeman B. et al. Analysis of epigenetic features characteristic of L1 loci expressed in human cells. Nucleic Acids Res. 50, 1888–1907 (2022). PubMed PMC

Shigaki H. et al. LINE-1 hypomethylation in noncancerous esophageal mucosae is associated with smoking history. Ann. Surg. Oncol. 19, 4238–4243 (2012). PubMed

Wangsri S., Subbalekha K., Kitkumthorn N. & Mutirangura A. Patterns and possible roles of LINE-1 methylation changes in smoke-exposed epithelia. PLoS One 7, e45292 (2012). PubMed PMC

Stueve T. R. et al. Epigenome-wide analysis of DNA methylation in lung tissue shows concordance with blood studies and identifies tobacco smoke-inducible enhancers. Hum. Mol. Genet. 26, 3014–3027 (2017). PubMed PMC

Caliri A. W., Caceres A., Tommasi S. & Besaratinia A. Hypomethylation of LINE-1 repeat elements and global loss of DNA hydroxymethylation in vapers and smokers. Epigenetics 15, 816–829 (2020). PubMed PMC

Camila B. et al. Genotoxicity and hypomethylation of LINE-1 induced by electronic cigarettes. Ecotoxicol. Environ. Saf. 256, 114900 (2023). PubMed

Joehanes R. et al. Epigenetic signatures of cigarette smoking. Circ. Cardiovasc. Genet. 9, 436–447 (2016). PubMed PMC

Yang P., Wang Y. & Macfarlan T. S. The Role of KRAB-ZFPs in Transposable Element Repression and Mammalian Evolution. Trends Genet. 33, 871–881 (2017). PubMed PMC

Imbeault M., Helleboid P.-Y. & Trono D. KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks. Nature 543, 550–554 (2017). PubMed

Han G. et al. An atlas of epithelial cell states and plasticity in lung adenocarcinoma. Nature 627, 656–663 (2024). PubMed PMC

Long E. et al. Context-aware single-cell multiome approach identified cell-type specific lung cancer susceptibility genes. bioRxiv (2023) doi:10.1101/2023.09.25.559336. DOI

de Tribolet-Hardy J. et al. Genetic features and genomic targets of human KRAB-zinc finger proteins. Genome Res. 33, 1409–1423 (2023). PubMed PMC

Del Toro N. et al. The IntAct database: efficient access to fine-grained molecular interaction data. Nucleic Acids Res. 50, D648–D653 (2022). PubMed PMC

Oleksiewicz U. et al. TRIM28 and interacting KRAB-ZNFs control self-renewal of human pluripotent stem cells through epigenetic repression of pro-differentiation genes. Stem Cell Reports 9, 2065–2080 (2017). PubMed PMC

Rosspopoff O. & Trono D. Take a walk on the KRAB side. Trends Genet. 39, 844–857 (2023). PubMed

Hill W. et al. Lung adenocarcinoma promotion by air pollutants. Nature 616, 159–167 (2023). PubMed PMC

Huang Z. et al. Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking. Nat. Genet. 54, 492–498 (2022). PubMed PMC

Colom B. et al. Mutant clones in normal epithelium outcompete and eliminate emerging tumours. Nature 598, 510–514 (2021). PubMed PMC

Jardim D. L., Goodman A., de Melo Gagliato D. & Kurzrock R. The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker. Cancer Cell 39, 154–173 (2021). PubMed PMC

Klein S. L. & Flanagan K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016). PubMed

Vaz M. et al. Chronic cigarette smoke-induced epigenomic changes precede sensitization of bronchial epithelial cells to single-step transformation by KRAS mutations. Cancer Cell 32, 360–376.e6 (2017). PubMed PMC

Mengs U. Tumour induction in mice following exposure to aristolochic acid. Arch. Toxicol. 61, 504–505 (1988). PubMed

Das S. et al. Aristolochic acid-associated cancers: a public health risk in need of global action. Nat. Rev. Cancer 22, 576–591 (2022). PubMed

Kazazian H. H. Jr & Goodier J. L. LINE drive. retrotransposition and genome instability. Cell 110, 277–280 (2002). PubMed

Gilbert N., Lutz-Prigge S. & Moran J. V. Genomic deletions created upon LINE-1 retrotransposition. Cell 110, 315–325 (2002). PubMed

Symer D. E. et al. Human l1 retrotransposition is associated with genetic instability in vivo. Cell 110, 327–338 (2002). PubMed

Li X. et al. Author Correction: LINE-1 transcription activates long-range gene expression. Nat. Genet. 56, 1762 (2024). PubMed

Sun Z. et al. LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer. Mol. Cancer 21, 147 (2022). PubMed PMC

Zhang X., Zhang R. & Yu J. New Understanding of the Relevant Role of LINE-1 Retrotransposition in Human Disease and Immune Modulation. Front Cell Dev Biol 8, 657 (2020). PubMed PMC

Beck C. R., Garcia-Perez J. L., Badge R. M. & Moran J. V. LINE-1 elements in structural variation and disease. Annu. Rev. Genomics Hum. Genet. 12, 187–215 (2011). PubMed PMC

Ambatipudi S. et al. Tobacco smoking-associated genome-wide DNA methylation changes in the EPIC study. Epigenomics 8, 599–618 (2016). PubMed

Breitling L. P., Yang R., Korn B., Burwinkel B. & Brenner H. Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. Am. J. Hum. Genet. 88, 450–457 (2011). PubMed PMC

Ringh M. V. et al. Tobacco smoking induces changes in true DNA methylation, hydroxymethylation and gene expression in bronchoalveolar lavage cells. EBioMedicine 46, 290–304 (2019). PubMed PMC

Kobayashi S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005). PubMed

Pao W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73 (2005). PubMed PMC

Hoyt S. J. et al. From telomere to telomere: The transcriptional and epigenetic state of human repeat elements. Science 376, eabk3112 (2022). PubMed PMC

Thawani A., Ariza A. J. F., Nogales E. & Collins K. Template and target-site recognition by human LINE-1 in retrotransposition. Nature 626, 186–193 (2024). PubMed PMC

Shah N. M. et al. Pan-cancer analysis identifies tumor-specific antigens derived from transposable elements. Nat. Genet. 55, 631–639 (2023). PubMed

Bergmann E. A., Chen B.-J., Arora K., Vacic V. & Zody M. C. Conpair: concordance and contamination estimator for matched tumor-normal pairs. Bioinformatics 32, 3196–3198 (2016). PubMed PMC

Pedersen B. S. et al. Somalier: rapid relatedness estimation for cancer and germline studies using efficient genome sketches. Genome Med. 12, 62 (2020). PubMed PMC

Nik-Zainal S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012). PubMed PMC

Sadedin S. P. & Oshlack A. Bazam: a rapid method for read extraction and realignment of high-throughput sequencing data. Genome Biol. 20, 78 (2019). PubMed PMC

Martínez-Jiménez F. et al. A compendium of mutational cancer driver genes. Nat. Rev. Cancer 20, 555–572 (2020). PubMed

Yuan K., Macintyre G., Liu W., PCAWG-11 working group & Markowetz, F. Ccube: A fast and robust method for estimating cancer cell fractions. bioRxiv 484402 (2018) doi:10.1101/484402. DOI

Yang L. et al. Diverse mechanisms of somatic structural variations in human cancer genomes. Cell 153, 919–929 (2013). PubMed PMC

Chen X. et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32, 1220–1222 (2016). PubMed

Muiños F., Martínez-Jiménez F., Pich O., Gonzalez-Perez A. & Lopez-Bigas N. In silico saturation mutagenesis of cancer genes. Nature 596, 428–432 (2021). PubMed

Chakravarty D. et al. OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol 2017, (2017). PubMed PMC

Bailey M. H. et al. Comprehensive Characterization of Cancer Driver Genes and Mutations. Cell 173, 371–385.e18 (2018). PubMed PMC

Cheng J. et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381, eadg7492 (2023). PubMed

Bergstrom E. N. et al. SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events. BMC Genomics 20, 685 (2019). PubMed PMC

Sondka Z. et al. COSMIC: a curated database of somatic variants and clinical data for cancer. Nucleic Acids Res. 52, D1210–D1217 (2024). PubMed PMC

Díaz-Gay M. et al. Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment. Bioinformatics 39, (2023). PubMed PMC

Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). PubMed PMC

Grossman R. L. et al. Toward a Shared Vision for Cancer Genomic Data. N. Engl. J. Med. 375, 1109–1112 (2016). PubMed PMC

Dobin A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013). PubMed PMC

Putri G. H., Anders S., Pyl P. T., Pimanda J. E. & Zanini F. Analysing high-throughput sequencing data in Python with HTSeq 2.0. Bioinformatics vol. 38 2943–2945 Preprint at 10.1093/bioinformatics/btac166 (2022). PubMed DOI PMC

Zhang Y., Parmigiani G. & Johnson W. E. ComBat-seq: batch effect adjustment for RNA-seq count data. NAR Genom Bioinform 2, lqaa078 (2020). PubMed PMC

Robinson M. D., McCarthy D. J. & Smyth G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010). PubMed PMC

McKerrow W. & Fenyö D. L1EM: a tool for accurate locus specific LINE-1 RNA quantification. Bioinformatics 36, 1167–1173 (2020). PubMed PMC

Long E. et al. Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes. Nat. Commun. 15, 7995 (2024). PubMed PMC

Reyes-Gopar H. et al. A single-cell transposable element atlas of human cell identity. Genomics (2023).

Müller F. et al. RnBeads 2.0: comprehensive analysis of DNA methylation data. Genome Biol. 20, 55 (2019). PubMed PMC

Leek J. T., Johnson W. E., Parker H. S., Jaffe A. E. & Storey J. D. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28, 882–883 (2012). PubMed PMC

Kawaguchi S., Higasa K., Shimizu M., Yamada R. & Matsuda F. HLA-HD: An accurate HLA typing algorithm for next-generation sequencing data. Hum. Mutat. 38, 788–797 (2017). PubMed

Reynisson B., Alvarez B., Paul S., Peters B. & Nielsen M. NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Res. 48, W449–W454 (2020). PubMed PMC

Schenck R. O., Lakatos E., Gatenbee C., Graham T. A. & Anderson A. R. A. NeoPredPipe: high-throughput neoantigen prediction and recognition potential pipeline. BMC Bioinformatics 20, 264 (2019). PubMed PMC

Thorsson V. et al. The Immune Landscape of Cancer. Immunity 48, 812–830.e14 (2018). PubMed PMC

Buffa F. M., Harris A. L., West C. M. & Miller C. J. Erratum: Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br. J. Cancer 103, 1136–1136 (2010). PubMed PMC

Winter S. C. et al. Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers. Cancer Res. 67, 3441–3449 (2007). PubMed

Ragnum H. B. et al. The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer. Br. J. Cancer 112, 382–390 (2015). PubMed PMC

Elvidge G. P. et al. Concordant Regulation of Gene Expression by Hypoxia and 2-Oxoglutarate-dependent Dioxygenase Inhibition: THE ROLE OF HIF-1α, HIF-2α, AND OTHER PATHWAYS*. J. Biol. Chem. 281, 15215–15226 (2006). PubMed

Sørensen B. S., Toustrup K., Horsman M. R., Overgaard J. & Alsner J. Identifying pH independent hypoxia induced genes in human squamous cell carcinomas in vitro. Acta Oncol. 49, 895–905 (2010). PubMed

Yates L. R. & Campbell P. J. Evolution of the cancer genome. Nat. Rev. Genet. 13, 795–806 (2012). PubMed PMC