Intratumor Heterogeneity: Evolution through Space and Time
Open accessAbstract
Recent technologic advances have permitted higher resolution and more rapid analysis of individual cancer genomes at the single-nucleotide level. Such advances have shown bewildering intertumor heterogeneity with limited somatic alterations shared between tumors of the same histopathologic subtype. Exacerbating such complexity, increasing evidence of intratumor genetic heterogeneity (ITH) is emerging, both within individual tumor biopsies and spatially separated between biopsies of the same tumor. Sequential analysis of tumors has also revealed evidence that ITH temporally evolves during the disease course. ITH has implications for predictive or prognostic biomarker strategies, where the tumor subclone that may ultimately influence therapeutic outcome may evade detection because of its absence or presence at low frequency at diagnosis or because of its regional separation from the tumor biopsy site. In this review, the implications of “trunk and branch” tumor evolution for drug discovery approaches and emerging evidence that low-frequency somatic events may drive tumor growth through paracrine signaling fostering a tumor ecologic niche are discussed. The concept of an “actionable mutation” is considered within a model of clonal dominance and heterogeneous tumor cell dependencies. Evidence that cancer therapeutics may augment ITH and the need to track the tumor subclonal architecture through treatment are defined as key research areas. Finally, if combination therapeutic approaches to limit the consequences of ITH prove challenging, identification of drivers or suppressors of ITH may provide attractive therapeutic targets to limit tumor evolutionary rates and adaptation. Cancer Res; 72(19); 4875–82. ©2012 AACR.
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?
Reproducibility of a tumor explant becomes an issue since a tumor is highly heterogeneous and varies between patients, between different tumors, or within the same tumor inside an individual patient.
“Conversely, the reproducibility of a tumor also becomes an issue since a tumor is highly heterogeneous and varies not only between patients but also between different tumors or even within the same tumor inside an individual patient [38].”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [38]
The Abstract describes heterogeneity between tumours and within individual tumours, and “Clinical Implications of ITH > A. Tumour Sampling Bias” explains how variation between sampled sites can complicate biomarker validation. The paper does not specifically address the reproducibility of tumour explants, so that application goes beyond what our copy establishes. (LLM, conf=0.83)
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
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989 · see citing works
Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing
Gerlinger, M., Rowan, A. J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1113205 · Cited by 7,774 · see citing works
Self-citationComprehensive genomic characterization defines human glioblastoma genes and core pathways
The Cancer Genome Atlas Research Network (2008) · Nature · doi:10.1038/nature07385 · Cited by 7,735 · see citing works
Nowell, P. C. (1976) · Science · doi:10.1126/science.959840 · Cited by 6,471 · see citing works
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from <i>BRCA</i> Mutation Carriers
Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0900212 · Cited by 3,634 · see citing works
Greaves, M., & Maley, C. C. (2012) · Nature · doi:10.1038/nature10762 · Cited by 3,162 · see citing works
Tumour evolution inferred by single-cell sequencing
Navin, N., Kendall, J., Troge, J., Andrews, P., Rodgers, L., McIndoo, J., Cook, K., Stepansky, A., Levy, D., Esposito, D., et al. (2011) · Nature · doi:10.1038/nature09807 · Cited by 2,598 · see citing works
Distant metastasis occurs late during the genetic evolution of pancreatic cancer
Yachida, S., Jones, S., Bozic, I., Antal, T., Leary, R., Fu, B., Kamiyama, M., Hruban, R. H., Eshleman, J. R., Nowak, M. A., et al. (2010) · Nature · doi:10.1038/nature09515 · Cited by 2,502 · see citing works
Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing
Ding, L., Ley, T. J., Larson, D. E., Miller, C. A., Koboldt, D. C., Welch, J. S., Ritchey, J. K., Young, M. A., Lamprecht, T., McLellan, M. D., et al. (2012) · Nature · doi:10.1038/nature10738 · Cited by 1,993 · see citing works
The clonal and mutational evolution spectrum of primary triple-negative breast cancers
Shah, S. P., Roth, A., Goya, R., Oloumi, A., Ha, G., Zhao, Y., Turashvili, G., Ding, J., Tse, K., Haffari, G., et al. (2012) · Nature · doi:10.1038/nature10933 · Cited by 1,967 · see citing works
Mutational Processes Molding the Genomes of 21 Breast Cancers
Nik-Zainal, S., Alexandrov, L. B., Wedge, D. C., Van Loo, P., Greenman, C. D., Raine, K., Jones, D., Hinton, J., Marshall, J., Stebbings, L. A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.024 · Cited by 1,909 · see citing works
The Life History of 21 Breast Cancers
Nik-Zainal, S., Van Loo, P., Wedge, D. C., Alexandrov, L. B., Greenman, C. D., Lau, K. W., Raine, K., Jones, D., Marshall, J., Ramakrishna, M., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.023 · Cited by 1,443 · see citing works
The patterns and dynamics of genomic instability in metastatic pancreatic cancer
Campbell, P. J., Yachida, S., Mudie, L. J., Stephens, P. J., Pleasance, E. D., Stebbings, L. A., Morsberger, L. A., Latimer, C., McLaren, S., Lin, M.-L., et al. (2010) · Nature · doi:10.1038/nature09460 · Cited by 1,317 · see citing works
Carter, S. L., Eklund, A. C., Kohane, I. S., Harris, L. N., & Szállási, Z. (2006) · Nature Genetics · doi:10.1038/ng1861 · Cited by 1,199 · see citing works
Genome remodelling in a basal-like breast cancer metastasis and xenograft
Ding, L., Ellis, M. J., Li, S., Larson, D. E., Chen, K., Wallis, J. W., Harris, C. C., McLellan, M. D., Fulton, R. S., Fulton, L., et al. (2010) · Nature · doi:10.1038/nature08989 · Cited by 1,134 · see citing works
Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution
Shah, S. P., Morin, R. D., Khattra, J. S., Prentice, L., Pugh, T. J., Burleigh, A., Delaney, A. D., Gelmon, K. A., Guliany, R., Senz, J., et al. (2009) · Nature · doi:10.1038/nature08489 · Cited by 1,063 · see citing works
Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC
Turke, A. B., Zejnullahu, K., Wu, Y.-L., Song, Y., Dias-Santagata, D., Lifshits, E., Toschi, L., Rogers, A., Mok, T., Sequist, L., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.11.022 · Cited by 1,059 · see citing works
Gatenby, R. A., Silva, A. S., Gillies, R. J., & Frieden, B. R. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3658 · Cited by 861 · see citing works
Genetic variegation of clonal architecture and propagating cells in leukaemia
Anderson, K., Lutz, C., van Delft, F. W., Bateman, C. M., Guo, Y., Colman, S., Kempski, H. M., Moorman, A. V., Titley, I., Swansbury, J. G., et al. (2010) · Nature · doi:10.1038/nature09650 · Cited by 803 · see citing works
Mosaic Amplification of Multiple Receptor Tyrosine Kinase Genes in Glioblastoma
Snuderl, M., Fazlollahi, L., Le, L. P., Nitta, M., Zhelyazkova, B. H., Davidson, C. J., Akhavanfard, S., Cahill, D. P., Aldape, K., Betensky, R. A., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.11.005 · Cited by 708 · see citing works
Genetic clonal diversity predicts progression to esophageal adenocarcinoma
Maley, C. C., Galipeau, P. C., Finley, J. C., Wongsurawat, V. J., Li, X., Sanchez, C. A., Paulson, T. G., Blount, P. L., Risques, R., Rabinovitch, P. S., et al. (2006) · Nature Genetics · doi:10.1038/ng1768 · Cited by 687 · see citing works
Evolutionary dynamics of carcinogenesis and why targeted therapy does not work
Gillies, R. J., Verduzco, D., & Gatenby, R. A. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3298 · Cited by 677 · see citing works
Clonal competition with alternating dominance in multiple myeloma
Keats, J. J., Chesi, M., Egan, J. B., Garbitt, V. M., Palmer, S. E., Braggio, E., Wier, S. V., Blackburn, P. R., Baker, A. S., Dispenzieri, A. A., et al. (2012) · Blood · doi:10.1182/blood-2012-01-405985 · Cited by 636 · see citing works
Poste, G. (2011) · Nature · doi:10.1038/469156a · Cited by 582 · see citing works
Inda, M.-D.-M., Bonavia, R., Mukasa, A., Narita, Y., Sah, D. W. Y., VandenBerg, S. R., Brennan, C. W., Johns, T. G., Bachoo, R. M., Hadwiger, P., et al. (2010) · Genes & Development · doi:10.1101/gad.1890510 · Cited by 543 · see citing works
Szerlip, N. J., Pedraza, A. M., Chakravarty, D., Azim, M., McGuire, J., Fang, Y., Ozawa, T., Holland, E. C., Huse, J. T., Jhanwar, S. C., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1114033109 · Cited by 538 · see citing works
Heterogeneity of kinase inhibitor resistance mechanisms in GIST
Liegl, B., Kepten, I., Le, C., Zhu, M. J., Demetri, G. D., Heinrich, M. C., Fletcher, C., Corless, C. L., & Fletcher, J. (2008) · The Journal of Pathology · doi:10.1002/path.2382 · Cited by 537 · see citing works
Inferring tumor progression from genomic heterogeneityPreprint
Navin, N. E., Krasnitz, A., Rodgers, L., Cook, K., Meth, J. L., Kendall, J., Riggs, M. G., Eberling, Y., Troge, J. E., Grubor, V. D., et al. (2009) · Genome Research · doi:10.1101/gr.099622.109 · Cited by 515 · see citing works
Su, K.-Y., Chen, H.-Y., Li, K.-C., Kuo, M.-L., Yang, J. C.-H., Chan, W.-K., Ho, B.-C., Chang, G.-C., Shih, J.-Y., Yu, S.-L., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.38.3224 · Cited by 499 · see citing works
Intratumor Heterogeneity: Seeing the Wood for the Trees
Yap, T. A., Gerlinger, M., Futreal, P. A., Pusztai, L., & Swanton, C. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003854 · Cited by 487 · see citing works
Self-citationHow Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine
Gerlinger, M., & Swanton, C. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605912 · Cited by 420 · see citing works
Self-citationClonal selection drives genetic divergence of metastatic medulloblastoma
Wu, X., Northcott, P. A., Dubuc, A. M., Dupuy, A. J., Shih, D. J. H., Witt, H., Croul, S. E., Bouffet, É., Fults, D. W., Eberhart, C. G., et al. (2012) · Nature · doi:10.1038/nature10825 · Cited by 408 · see citing works
A change of strategy in the war on cancer
Gatenby, R. A. (2009) · Nature · doi:10.1038/459508a · Cited by 406 · see citing works
Cancer chromosomal instability: therapeutic and diagnostic challenges
McGranahan, N., Burrell, R. A., Endesfelder, D., Novelli, M. R., & Swanton, C. (2012) · EMBO Reports · doi:10.1038/embor.2012.61 · Cited by 377 · see citing works
Self-citationParadoxical Relationship between Chromosomal Instability and Survival Outcome in Cancer
Birkbak, N. J., Eklund, A. C., Li, Q., McClelland, S. E., Endesfelder, D., Tan, P. B. O., Tan, I. B., Richardson, A. L., Szállási, Z., & Swanton, C. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-3667 · Cited by 339 · see citing works
Self-citationMetastatic variants are generated spontaneously at a high rate in mouse KHT tumor.
Harris, J. F., Chambers, A. F., Hill, R. P., & Ling, V. W. T. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.18.5547 · Cited by 137 · see citing works
Gatenby, R. A., Gillies, R. J., & Brown, J. S. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3036 · Cited by 100 · see citing works
Generation of drug-resistant variants in metastatic B16 mouse melanoma cell lines.
Cillo, C., Dick, J. E., Ling, V., et al. (1987) · PubMed · Cited by 83 · see citing works
Characterizing Mutational Heterogeneity in a Glioblastoma Patient with Double Recurrence
Nickel, G. C., Barnholtz‐Sloan, J. S., Gould, M. P., McMahon, S., Cohen, A. J., Adams, M. D., Guda, K., Cohen, M. L., Sloan, A. E., & LaFramboise, T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035262 · Cited by 79 · see citing works
Swanton, C., Larkin, J., Gerlinger, M., Eklund, A. C., Howell, M. T., Stamp, G., Downward, J., Gore, M. E., Futreal, P. A., Escudier, B. J., et al. (2010) · Genome Medicine · doi:10.1186/gm174 · Cited by 45 · see citing works
Self-citationGrade and flow cytometric analysis of ploidy for infiltrating ductal carcinomas
Frierson, H. F. (1993) · Human Pathology · doi:10.1016/0046-8177(93)90058-o · Cited by 27 · see citing works
Vaziri, S. A. J., Tavares, E. J., Golshayan, A., Rini, B. I., Aydın, H., Zhou, M., Sercia, L., Wood, L. S., Ganapathi, M. K., Bukowski, R. M., et al. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00051 · Cited by 19 · see citing works
'Exploring aneuploidy: the significance of chromosomal imbalance' review series
Holland, A. J., & Cleveland, D. W. (2012) · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Cancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681 · see citing works
Roles of the immune system in cancer: From tumor initiation to metastatic progression
Gonzalez, H., Hagerling, C., & Werb, Z. (2018) · Genes & Development · doi:10.1101/gad.314617.118 · Cited by 2,111 · see citing works
Eleven grand challenges in single-cell data science
Lähnemann, D., Köster, J., Szczurek, E., McCarthy, D. J., Hicks, S. C., Robinson, M. D., Vallejos, C. A., Campbell, K. R., Beerenwinkel, N., Mahfouz, A., et al. (2020) · Genome Biology · doi:10.1186/s13059-020-1926-6 · Cited by 1,327 · see citing works
Biological and therapeutic impact of intratumor heterogeneity in cancer evolution
McGranahan, N., & Swanton, C. (2015) · Cancer Cell · doi:10.1016/j.ccell.2014.12.001 · Cited by 1,077 · see citing works
Self-citationIntratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing
Zhang, J., Fujimoto, J., Zhang, J., Wedge, D. C., Song, X., Zhang, J., Seth, S., Chow, C.-W., Cao, Y., Gumbs, C., et al. (2014) · Science · doi:10.1126/science.1256930 · Cited by 965 · see citing works
Hou, Y., Guo, H., Cao, C., Li, X., Hu, B., Zhu, P., Wu, X., Wen, L., Tang, F., Huang, Y., et al. (2016) · Cell Research · doi:10.1038/cr.2016.23 · Cited by 647 · see citing works
Lanman, R. B., Mortimer, S. A., Zill, O. A., Sebisanovic, D., Lopez, R., Blau, S., Collisson, E. A., Divers, S. G., Hoon, D. S. B., Kopetz, E. S., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0140712 · Cited by 695 · see citing works
“Temporal heterogeneity may occur by linear evolution or by competition between different subclones in the same tumor that compete with each other for dominance during the disease course or under pressure from targeted therapies [11].”
BackgroundImaging Intratumor Heterogeneity: Role in Therapy Response, Resistance, and Clinical Outcome
O'Connor, J. P. B., Rose, C. J., Waterton, J. C., Carano, R. A. D., Parker, G. J. M., & Jackson, A. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0990 · Cited by 677 · see citing works
Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor
Juric, D., Castel, P., Griffith, M., Griffith, O. L., Won, H. H., Ellis, H., Ebbesen, S. H., Ainscough, B. J., Ramu, A., Iyer, G., et al. (2015) · Nature · doi:10.1038/nature13948 · Cited by 588 · see citing works
The Influence of Metabolism on Drug Response in Cancer
Zaal, E. A., & Berkers, C. R. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00500 · Cited by 272 · see citing works
Zi, Y., Yang, K., He, J., Wu, Z., Liu, J., & Zhang, W. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114449 · Cited by 268 · see citing works
Microfluidic modelling of the tumor microenvironment for anti-cancer drug development
Shang, M., Soon, R. H., Lim, C. T., Khoo, B. L., & Han, J. (2019) · Lab on a Chip · doi:10.1039/c8lc00970h · Cited by 227 · see citing works
Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view
Lu, S., Jang, H., Gu, S., Zhang, J., & Nussinov, R. (2016) · Chemical Society Reviews · doi:10.1039/c5cs00911a · Cited by 188 · see citing works
Genovese, I., Ilari, A., Assaraf, Y. G., Fazi, F., & Colotti, G. (2017) · Drug Resistance Updates · doi:10.1016/j.drup.2017.10.003 · Cited by 156 · see citing works
Single-cell mutational profiling and clonal phylogeny in cancer
Potter, N. E., Ermini, L., Papaemmanuil, E., Cazzaniga, G., Vijayaraghavan, G., Titley, I., Ford, A., Campbell, P., Kearney, L., & Greaves, M. (2013) · Genome Research · doi:10.1101/gr.159913.113 · Cited by 107 · see citing works
Is cancer gene therapy an empty suit?
Brenner, M. K., Gottschalk, S., Leen, A. M., & Vera, J. F. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70173-6 · Cited by 52 · see citing works
- Authors
- Swanton, C.
- Affiliations
- Cancer Research UK (GB)
- Corresponding author
- Swanton, Charles
- ORCID
- Swanton, Charles
- Venue
- Cancer Research
- Published
- 2012-09-30
- Volume
- 72
- Issue
- 19
- Pages
- 4875-4882
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3712191
- OpenAlex
- W2139790154
- Semantic Scholar
- e2eab6fa58ba25ed951e0184d9a602ced2af420f
- Cited by
- 931
- References
- 43
- Citations by year
- 2026: 37 · 2025: 31 · 2024: 40 · 2023: 66 · 2022: 64 · 2021: 74 · 2020: 61 · 2019: 72 · 2018: 83 · 2017: 93 · 2016: 93 · 2015: 81 · 2014: 85 · 2013: 44 · 2012: 4
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- intratumoral heterogeneity, tumor evolution, clonal evolution, tumor subclones, somatic mutations, actionable mutations, clonal dominance, tumor microenvironment, paracrine signaling, drug resistance, predictive biomarkers, combination therapy, cancer genomics
- MeSH terms
- Antineoplastic Agents, Chromosome Aberrations, Humans, Models, Genetic, Mutation, Neoplasms, Time Factors, Genetic Heterogeneity, Drug Resistance, Neoplasm, Evolution, Molecular
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
