The mutational footprints of cancer therapies
Open accessPublished version of a preprint
Abstract
Some cancer therapies damage DNA and cause mutations in both cancerous and healthy cells. Therapy-induced mutations may underlie some of the long-term and late side effects of treatments, such as mental disabilities, organ toxicity and secondary neoplasms. Nevertheless, the burden of mutation contributed by different chemotherapies has not been explored. Here we identify the mutational signatures or footprints of six widely used anticancer therapies across more than 3,500 metastatic tumors originating from different organs. These include previously known and new mutational signatures generated by platinum-based drugs as well as a previously unknown signature of nucleoside metabolic inhibitors. Exploiting these mutational footprints, we estimate the contribution of different treatments to the mutation burden of tumors and their risk of contributing coding and potential driver mutations in the genome. The mutational footprints identified here allow for precise assessment of the mutational risk of different cancer therapies to understand their long-term side effects. Analysis of whole-genome sequences from more than 3,500 metastatic tumors identifies mutational signatures associated with different chemotherapies and provides estimates of the relative contribution of different treatments to tumor mutational burden.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Common cancer treatments in general do not induce mutations that may interfere with CHORD predictions.
“Two recent studies showed that common cancer treatments in general do not induce mutations that may interfere with CHORD predictions16,17.”
From Pan-cancer landscape of homologous recombination deficiency. (2020) · cites this paper as [16]
The Results section, “The mutational footprints of six anti-cancer therapies,” identifies mutational signatures caused by widely used platinum-based treatments, contrary to the claim that common treatments generally do not induce mutations. The paper does not assess whether treatment-induced mutations interfere with CHORD predictions, so that specific effect cannot be judged from this source. (LLM, conf=0.83)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredRadiotherapy has the potential to induce deletions with flanking microhomology, which could lead to false-positive HRD classifications.
“However, these two studies (as well as one by Behjati et al.18) did show that radiotherapy had the potential to induce deletions with flanking microhomology, which could potentially lead to false-positive HRD classifications.”
From Pan-cancer landscape of homologous recombination deficiency. (2020) · cites this paper as [16]
The Results (page unavailable) report higher activity of a radiation-associated insertion/deletion signature in irradiated tumors, including HR-proficient tumors. Extended Data Fig. 4 also links that signature to HR deficiency. Neither passage specifies deletions with flanking microhomology or says that radiotherapy could cause false-positive HRD classifications. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe most common cancer treatments have been shown to have little or no contribution to microhomology deletions, with the exception of radiotherapy.
“The most common cancer treatments have been shown to have little or no contribution to microhomology deletions, with the exception of radiotherapy16–18.”
From Pan-cancer landscape of homologous recombination deficiency. (2020) · cites this paper as [16]
The Results (page unavailable) report an indel signature associated with radiation and higher activity in irradiated than non-irradiated tumors. They do not identify that signature as microhomology deletions or show that common treatments make little or no contribution to those deletions. The Discussion (page unavailable) also cautions that other treatment associations may have gone undetected. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041 · see citing works
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400 · see citing works
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400 · see citing works
Signatures of mutational processes in human cancer
Initiative, A. P. C. G., Alexandrov, L. B., ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, PedBrain, I., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. V., et al. (2013) · Nature · doi:10.1038/nature12477 · Cited by 9,660 · see citing works
Julia: A Fresh Approach to Numerical Computing
Bezanson, J., Edelman, A. S., Karpinski, S., & Shah, V. B. (2017) · SIAM Review · doi:10.1137/141000671 · Cited by 6,104 · see citing works
Florea, A.-M., & Büsselberg, D. (2011) · Cancers · doi:10.3390/cancers3011351 · Cited by 1,759 · see citing works
The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers
Sondka, Z., Bamford, S., Cole, C. G., Ward, S. A., Dunham, I., & Forbes, S. A. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0060-1 · Cited by 1,597 · see citing works
Somatic mutation in cancer and normal cells
Martincorena, I., & Campbell, P. J. (2015) · Science · doi:10.1126/science.aab4082 · Cited by 1,396 · see citing works
Deciphering Signatures of Mutational Processes Operative in Human Cancer
Alexandrov, L. B., Nik‐Zainal, S., Wedge, D. C., Campbell, P. J., & Stratton, M. R. (2013) · Cell Reports · doi:10.1016/j.celrep.2012.12.008 · Cited by 1,277 · see citing works
Rosenthal, R., McGranahan, N., Herrero, J., Taylor, B. S., & Swanton, C. (2016) · Genome biology · doi:10.1186/s13059-016-0893-4 · Cited by 1,217 · see citing works
Pan-cancer whole-genome analyses of metastatic solid tumours
Priestley, P., Baber, J., Lolkema, M. P., Steeghs, N., de Bruijn, E., Shale, C., Duyvesteyn, K., Haidari, S., van Hoeck, A., Onstenk, W., et al. (2019) · Nature · doi:10.1038/s41586-019-1689-y · Cited by 1,106 · see citing works
Self-citationMutational signatures associated with tobacco smoking in human cancer
Alexandrov, L. B., Ju, Y. S., Haase, K., Van Loo, P., Martincorena, I., Nik-Zainal, S., Totoki, Y., Fujimoto, A., Nakagawa, H., Shibata, T., et al. (2016) · Science · doi:10.1126/science.aag0299 · Cited by 1,100 · see citing works
Transcription-coupled DNA repair: two decades of progress and surprises
Hanawalt, P. C., & Spivak, G. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2549 · Cited by 1,038 · see citing works
Clock-like mutational processes in human somatic cells
Alexandrov, L. B., Jones, P. H., Wedge, D. C., Sale, J. E., Campbell, P. J., Nik‐Zainal, S., & Stratton, M. R. (2015) · Nature Genetics · doi:10.1038/ng.3441 · Cited by 1,038 · see citing works
Candidate mechanisms for chemotherapy-induced cognitive changes
Ahles, T. A., & Saykin, A. J. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2073 · Cited by 924 · see citing works
Mechanisms underlying mutational signatures in human cancers
Helleday, T., Eshtad, S., & Nik‐Zainal, S. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3729 · Cited by 841 · see citing works
Clonal evolution of glioblastoma under therapy
Wang, J., Cazzato, E., Ladewig, E., Frattini, V., Rosenbloom, D. I. S., Zairis, S., Abate, F., Liu, Z., Elliott, O., Shin, Y., et al. (2016) · Nature Genetics · doi:10.1038/ng.3590 · Cited by 759 · see citing works
The landscape of somatic mutation in normal colorectal epithelial cells
Lee-Six, H., Olafsson, S., Ellis, P., Osborne, R. J., Sanders, M. A., Moore, L., Georgakopoulos, N., Torrente, F., Noorani, A., Goddard, M., et al. (2019) · Nature · doi:10.1038/s41586-019-1672-7 · Cited by 747 · see citing works
A Compendium of Mutational Signatures of Environmental Agents
Kucab, J. E., Zou, X., Morganella, S., Joel, M., Nanda, A. S., Nagy, E., Gomez, C., Degasperi, A., Harris, R., Jackson, S. P., et al. (2019) · Cell · doi:10.1016/j.cell.2019.03.001 · Cited by 660 · see citing works
Lange, S. S., Takata, K.-I., & Wood, R. D. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2998 · Cited by 615 · see citing works
The Repertoire of Mutational Signatures in Human CancerPreprint
Alexandrov, L. B., Kim, J., Haradhvala, N. J., Huang, M. N., Ng, A. W. T., Wu, Y., Boot, A., Covington, K. R., Gordenin, D. A., Bergstrom, E. N., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/322859 · Cited by 529 · see citing works
Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors
Kim, J., Mouw, K. W., Polak, P. P., Braunstein, L. Z., Kamburov, A., Tiao, G., Kwiatkowski, D. J., Rosenberg, J. E., Allen, E. M. V., D’Andrea, A. D., et al. (2016) · Nature Genetics · doi:10.1038/ng.3557 · Cited by 402 · see citing works
Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair
Haradhvala, N. J., Polak, P. P., Stojanov, P., Covington, K. R., Shinbrot, E., Hess, J. M., Rheinbay, E., Kim, J., Maruvka, Y. E., Braunstein, L. Z., et al. (2016) · Cell · doi:10.1016/j.cell.2015.12.050 · Cited by 387 · see citing works
Radiation induced secondary malignancies: a review article
Dracham, C. B., Shankar, A., & Madan, R. (2018) · Radiation Oncology Journal · doi:10.3857/roj.2018.00290 · Cited by 351 · see citing works
Cancer-treatment-induced neurotoxicity—focus on newer treatments
Stone, J. B., & DeAngelis, L. M. (2015) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.152 · Cited by 276 · see citing works
Mutational signatures of ionizing radiation in second malignancies
Behjati, S., Gundem, G., Wedge, D. C., Roberts, N. D., Tarpey, P. S., Cooke, S. L., Van Loo, P., Alexandrov, L. B., Ramakrishna, M., Davies, H., et al. (2016) · Nature Communications · doi:10.1038/ncomms12605 · Cited by 274 · see citing works
The topography of mutational processes in breast cancer genomes
Morganella, S., Alexandrov, L. B., Głodzik, D., Zou, X., Davies, H. R., Staaf, J., Sieuwerts, A. M., Brinkman, A. B., Martin, S., Ramakrishna, M., et al. (2016) · Nature Communications · doi:10.1038/ncomms11383 · Cited by 252 · see citing works
Kasar, S. N., Kim, J., Improgo, R., Tiao, G., Polak, P. P., Haradhvala, N. J., Lawrence, M. S., Kieżun, A., Fernandes, S. M., Bahl, S., et al. (2015) · Nature Communications · doi:10.1038/ncomms9866 · Cited by 248 · see citing works
Participation of DNA repair in the response to 5-fluorouracil
Wyatt, M. D., & Wilson, D. M. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8557-5 · Cited by 245 · see citing works
Treatment-related cardiotoxicity in survivors of childhood cancer
Lipshultz, S. E., Cochran, T. R., Franco, V. I., & Miller, T. L. (2013) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2013.195 · Cited by 234 · see citing works
The genome as a record of environmental exposure
Nik‐Zainal, S., Kucab, J. E., Morganella, S., Głodzik, D., Alexandrov, L. B., Arlt, V. M., Weninger, A., Hollstein, M. C., Stratton, M. R., & Phillips, D. H. (2015) · Mutagenesis · doi:10.1093/mutage/gev073 · Cited by 215 · see citing works
Structural basis for the initiation of eukaryotic transcription-coupled DNA repair
Xu, J., Lahiri, I., Wang, W., Wier, A. D., Cianfrocco, M. A., Chong, J. P. C., Hare, A. A., Dervan, P. B., DiMaio, F., Leschziner, A. E., et al. (2017) · Nature · doi:10.1038/nature24658 · Cited by 202 · see citing works
Iyer, N. S., Balsamo, L. M., Bracken, M. B., & Kadan-Lottick, N. S. (2015) · Blood · doi:10.1182/blood-2015-02-627414 · Cited by 194 · see citing works
A comprehensive survey of the mutagenic impact of common cancer cytotoxics
Szikriszt, B., Póti, Á., Pipek, O., Krzystanek, M., Kanu, N., Molnár, J., Ribli, D., Szeltner, Z., Tusnády, G., Csabai, I., et al. (2016) · Genome biology · doi:10.1186/s13059-016-0963-7 · Cited by 181 · see citing works
Boot, A., Huang, M. N., Ng, A. W. T., Ho, S.-C., Lim, J. Q., Kawakami, Y., Chayama, K., Teh, B. T., Nakagawa, H., & Rozen, S. (2018) · Genome Research · doi:10.1101/gr.230219.117 · Cited by 173 · see citing works
Breast cancer therapy-associated cardiovascular disease
Zagar, T. M., Cardinale, D. M., & Marks, L. B. (2015) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.171 · Cited by 152 · see citing works
Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer
Liu, D., Abbosh, P. H., Keliher, D., Reardon, B. M., Miao, D., Mouw, K. W., Taylor-Weiner, A. N., Wankowicz, S. A. M., Han, G. C., Teo, M. Y., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02320-7 · Cited by 151 · see citing works
Mutational signature distribution varies with DNA replication timing and strand asymmetry
Tomkova, M., Tomek, J., Kriaucionis, S., & Schuster-Böckler, B. (2018) · Genome Biology · doi:10.1186/s13059-018-1509-y · Cited by 137 · see citing works
The landscape of somatic mutation in normal colorectal epithelial cellsPreprint
Lee-Six, H., Ellis, P., Osborne, R. J., Sanders, M. A., Moore, L., Georgakopoulos, N., Torrente, F., Noorani, A., Goddard, M. J., Robinson, P. S., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/416800 · Cited by 128 · see citing works
Pich, O., Muiños, F., Sabarinathan, R., Reyes-Salazar, I., Gonzalez-Perez, A., & Lopez-Bigas, N. (2018) · Cell · doi:10.1016/j.cell.2018.10.004 · Cited by 123 · see citing works
Self-citationSecondary Malignancies Following Cancer Chemotherapy
Boffetta, P., & Kaldor, J. M. (1994) · Acta Oncologica · doi:10.3109/02841869409121767 · Cited by 118 · see citing works
Secondary malignancies in pediatric cancer survivors: Perspectives and review of the literature
Choi, D. K., Helenowski, I., & Hijiya, N. (2014) · International Journal of Cancer · doi:10.1002/ijc.28991 · Cited by 116 · see citing works
Poon, S. L., McPherson, J. R., Tan, P. B. O., Teh, B. T., & Rozen, S. (2014) · Genome Medicine · doi:10.1186/gm541 · Cited by 106 · see citing works
The Clonal Evolution of Metastatic Osteosarcoma as Shaped by Cisplatin Treatment
Brady, S. W., Ma, X., Bahrami, A., Satas, G., Wu, G., Newman, S., Rusch, M., Putnam, D. K., Mulder, H. L., Yergeau, D. A., et al. (2019) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-18-0620 · Cited by 52 · see citing works
The evolutionary history of 2,658 cancersPreprint
Gerstung, M., Jolly, C., Leshchiner, I., Dentro, S. C., González, S., Rosebrock, D., Mitchell, T. J., Rubanova, Y., Anur, P., Yu, K., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/161562 · Cited by 51 · see citing works
Late Effects in Adult Survivors of Pediatric Cancer: A Guide for the Primary Care Physician
Kopp, L. M., Gupta, P., Pelayo-Katsanis, L., et al. (2012) · The American Journal of Medicine · doi:10.1016/j.amjmed.2012.01.013 · Cited by 49 · see citing works
van der Plas, E. A. A., Nieman, B. J., Butcher, D. T., Hitzler, J. K., Weksberg, R., Ito, S., & Schachar, R. J. (2015) · Europe PMC (PubMed Central) · Cited by 40 · see citing works
Ritt, J., Raymond, F., Leprohon, P., et al. (2013) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0002564 · Cited by 30 · see citing works
Pan-cancer whole genome analyses of metastatic solid tumorsPreprint
Priestley, P., Baber, J., Lolkema, M. P., Steeghs, N., de Bruijn, E., Shale, C., Duyvesteyn, K., Haidari, S., van Hoeck, A., Onstenk, W., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/415133 · Cited by 27 · see citing works
Self-citationSegovia, R., Shen, Y., Lujan, S. A., Jones, S. J. M., & Stirling, P. C. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1618555114 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Pan-cancer landscape of homologous recombination deficiency.
Nguyen, L., W. M. Martens, J., Van Hoeck, A., & Cuppen, E. (2020) · Nature communications · doi:10.1038/s41467-020-19406-4 · Cited by 532 · see citing works
The genomics of oxidative DNA damage, repair, and resulting mutagenesis
Poetsch, A. R. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.12.013 · Cited by 420 · see citing works
Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data
Connor, A. A., & Gallinger, S. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-021-00418-1 · Cited by 369 · see citing works
Increased somatic mutation burdens in normal human cells due to defective DNA polymerases
Robinson, P. S., Coorens, T. H. H., Palles, C., Mitchell, E., Abascal, F., Olafsson, S., Lee, B. C. H., Lawson, A. R. J., Lee-Six, H., Moore, L., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00930-y · Cited by 173 · see citing works
- Authors
- Pich, O., Muiños, F., Lolkema, M. P., Steeghs, N., Gonzalez-Perez, A., & Lopez-Bigas, N.
- Affiliations
- Institute for Research in Biomedicine (ES)
- Erasmus MC (NL)
- The Netherlands Cancer Institute (NL)
- ORCID
- Venue
- Nature Genetics
- Published
- 2019-11-18
- Volume
- 51
- Issue
- 12
- Pages
- 1732-1740
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6887544
- OpenAlex
- W2983330893
- Semantic Scholar
- 31599512e5cfc997e87d392196aeda78bdc7c8c7
- Cited by
- 309
- References
- 50
- Citations by year
- 2026: 35 · 2025: 39 · 2024: 37 · 2023: 55 · 2022: 47 · 2021: 61 · 2020: 33 · 2019: 2
- FWCI
- 11.31
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Institute for Research in Biomedicine
- Centres de Recerca de Catalunya
- Barcelona Institute of Science and Technology
- Generalitat de Catalunya
- Ministerio de Economía y Competitividad (RYC2013-14554, SAF2015-66084-R)
- Universitair Medisch Centrum Utrecht
- H2020 European Research Council (682398)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- mutational signatures, cancer chemotherapy, platinum drugs, tumor mutational burden, metastatic cancer, secondary malignancies, treatment side effects, driver mutations, whole genome sequencing
- MeSH terms
- Antineoplastic Agents, Humans, Mutation, Neoplasms, Radiotherapy, Risk Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
