Clonal expansion in non-cancer tissues
Abstract
Cancer is a clonal disorder derived from a single ancestor cell and its progenies that are positively selected by acquisition of 'driver mutations'. However, the evolution of positively selected clones does not necessarily imply the presence of cancer. On the contrary, it has become clear that expansion of these clones in phenotypically normal or non-cancer tissues is commonly seen in association with ageing and/or in response to environmental insults and chronic inflammation. Recent studies have reported expansion of clones harbouring mutations in cancer driver genes in the blood, skin, oesophagus, bronchus, liver, endometrium and bladder, where the expansion could be so extensive that tissues undergo remodelling of an almost entire tissue. The presence of common cancer driver mutations in normal tissues suggests a strong link to cancer development, providing an opportunity to understand early carcinogenic processes. Nevertheless, some driver mutations are unique to normal tissues or have a mutation frequency that is much higher in normal tissue than in cancer, indicating that the respective clones may not necessarily be destined for evolution to cancer but even negatively selected for carcinogenesis depending on the mutated gene. Moreover, tissues that are remodelled by genetically altered clones might define functionalities of aged tissues or modified inflammatory processes. In this Review, we provide an overview of major findings on clonal expansion in phenotypically norm…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Across most, if not all, tissues, after an initial expansion of the stem cell pool during early life, clonal heterogeneity tends to diminish over time.
“A consistent pattern has been observed across most, if not all, tissues: after an initial expansion of the stem cell pool during early life, clonal heterogeneity tends to diminish over time (Figure 1).17-24”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [20]
Selected and more fit clones may share genomic events such as nonsynonymous mutations initially thought to be restricted to cancer.
“Interestingly, these selected and more fit clones may share genomic events such as nonsynonymous mutations initially thought to be restricted to cancer.17-24”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [20]
Cites
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
Sequencing technologies – the next generation
Metzker, M. L. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2626 · Cited by 7,066 · see citing works
Age-related clonal hematopoiesis associated with adverse outcomes
Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408617 · Cited by 4,841 · see citing works
Genomic classification and prognosis in acute myeloid leukemia
Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V. I., Paschka, P., Roberts, N. D., Potter, N. E., Heuser, M., Thol, F., Bolli, N., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1516192 · Cited by 4,350 · see citing works
Greaves, M., & Maley, C. C. (2012) · Nature · doi:10.1038/nature10762 · Cited by 3,162 · see citing works
Pan-cancer analysis of whole genomes
The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium, Aaltonen, L. A., Abascal, F., Abeshouse, A., Aburatani, H., Adams, D. J., Agrawal, N., Ahn, K. S., Ahn, S.-M., Aikata, H., et al. (2020) · Nature · doi:10.1038/s41586-020-1969-6 · Cited by 3,064 · see citing works
Clonal heterogeneity and tumor evolution: past, present, and the future
McGranahan, N., & Swanton, C. (2017) · Cell · doi:10.1016/j.cell.2017.01.018 · Cited by 2,840 · 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
Comprehensive Characterization of Cancer Driver Genes and Mutations
Bailey, M. H., Tokheim, C., Porta-Pardo, E., Sengupta, S., Bertrand, D., Weerasinghe, A., Colaprico, A., Wendl, M. C., Kim, J., Reardon, B., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.060 · Cited by 2,256 · see citing works
Landscape of somatic mutations in 560 breast cancer whole-genome sequences
Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., Zou, X., Martincorena, I., Alexandrov, L. B., Martin, S., Wedge, D. C., et al. (2016) · Nature · doi:10.1038/nature17676 · Cited by 2,218 · see citing works
Mechanisms of DNA damage, repair, and mutagenesis
Chatterjee, N., & Walker, G. C. (2017) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22087 · Cited by 2,039 · see citing works
Drost, J., & Clevers, H. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0007-6 · Cited by 1,790 · see citing works
The origin and evolution of mutations in acute myeloid leukemia
Welch, J. S., Ley, T. J., Link, D. C., Miller, C. A., Larson, D. E., Koboldt, D. C., Wartman, L. D., Lamprecht, T. L., Liu, F., Xia, J., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.023 · Cited by 1,575 · see citing works
Landscape of genetic lesions in 944 patients with myelodysplastic syndromes
Haferlach, T., Nagata, Y., Grossmann, V, Okuno, Y., Bacher, U., Nagae, G., Schnittger, S., Sanada, M., Kon, A., Alpermann, T., et al. (2014) · Leukemia · doi:10.1038/leu.2013.336 · Cited by 1,532 · see citing works
Self-citationEpigenetic plasticity and the hallmarks of cancer
Flavahan, W. A., Gaskell, E., & Bernstein, B. E. (2017) · Science · doi:10.1126/science.aal2380 · Cited by 1,340 · see citing works
Clonal hematopoiesis in human aging and disease
Jaiswal, S., & Ebert, B. L. (2019) · Science · doi:10.1126/science.aan4673 · Cited by 1,156 · see citing works
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution
de Bruin, E. C., McGranahan, N., Mitter, R., Salm, M., Wedge, D. C., Yates, L., Jamal-Hanjani, M., Shafi, S., Murugaesu, N., Rowan, A. J., et al. (2014) · Science · doi:10.1126/science.1253462 · Cited by 1,117 · see citing works
Tissue-specific mutation accumulation in human adult stem cells during life
Blokzijl, F., de Ligt, J., Jager, M., Sasselli, V., Roerink, S., Sasaki, N., Huch, M., Boymans, S., Kuijk, E., Prins, P., et al. (2016) · Nature · doi:10.1038/nature19768 · Cited by 935 · see citing works
Heterogeneity of genomic evolution and mutational profiles in multiple myeloma
Bolli, N., Avet-Loiseau, H., Wedge, D. C., Van Loo, P., Alexandrov, L. B., Martincorena, I., Dawson, K. J., Iorio, F., Nik-Zainal, S., Bignell, G. R., et al. (2014) · Nature Communications · doi:10.1038/ncomms3997 · Cited by 875 · see citing works
Prediction of acute myeloid leukaemia risk in healthy individuals
Abelson, S., Collord, G., Ng, S. W. K., Weissbrod, O., Mendelson Cohen, N., Niemeyer, E., Barda, N., Zuzarte, P. C., Heisler, L., Sundaravadanam, Y., et al. (2018) · Nature · doi:10.1038/s41586-018-0317-6 · Cited by 850 · see citing works
Trans-ancestry mutational landscape of hepatocellular carcinoma genomes
Totoki, Y., Tatsuno, K., Covington, K. R., Ueda, H., Creighton, C. J., Kato, M., Tsuji, S., Donehower, L. A., Slagle, B. L., Nakamura, H., et al. (2014) · Nature Genetics · doi:10.1038/ng.3126 · Cited by 781 · see citing works
Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults
Young, A. L., Challen, G. A., Birmann, B. M., & Druley, T. E. (2016) · Nature Communications · doi:10.1038/ncomms12484 · Cited by 692 · see citing works
Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma
Northcott, P. A., Lee, C., Zichner, T., Stütz, A. M., Erkek, S., Kawauchi, D., Shih, D. J. H., Hovestadt, V., Zapatka, M., Sturm, D., et al. (2014) · Nature · doi:10.1038/nature13379 · Cited by 642 · see citing works
Age-related remodelling of oesophageal epithelia by mutated cancer drivers
Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., Shiozawa, Y., Sato, Y., Aoki, K., Kim, S. K., et al. (2019) · Nature · doi:10.1038/s41586-018-0811-x · Cited by 628 · see citing works
Somatic mutations precede acute myeloid leukemia years before diagnosis
Desai, P., Mencia-Trinchant, N., Savenkov, O., Simon, M. S., Cheang, G., Lee, S., Samuel, M., Ritchie, E. K., Guzman, M. L., Ballman, K. V., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0081-z · Cited by 619 · see citing works
Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age
Busque, L., Mio, R., Mattioli, J., Brais, E., Blais, N., Lalonde, Y., Maragh, M., & Gilliland, D. (1996) · Blood · doi:10.1182/blood.v88.1.59.59 · Cited by 543 · see citing works
High Prevalence of Mucosa-Associated E. coli Producing Cyclomodulin and Genotoxin in Colon Cancer
Buc, E., Dubois, D., Sauvanet, P., Raisch, J., Delmas, J., Darfeuille-Michaud, A., Pezet, D., & Bonnet, R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056964 · Cited by 535 · see citing works
Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis
McKerrell, T., Park, N., Moreno, T., Grove, C. S., Ponstingl, H., Stephens, J., Crawley, C., Craig, J., Scott, M. A., Hodkinson, C., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.005 · Cited by 534 · see citing works
Mitochondrial DNA mutations in human colonic crypt stem cells
Taylor, R. W., Barron, M. J., Borthwick, G. M., Gospel, A., Chinnery, P. F., Samuels, D. C., Taylor, G. A., Plusa, S. M., Needham, S. J., Greaves, L. C., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci19435 · Cited by 530 · see citing works
The mutational landscape of normal human endometrial epithelium
Moore, L., Leongamornlert, D., Coorens, T. H. H., Sanders, M. A., Ellis, P., Dentro, S. C., Dawson, K. J., Butler, T., Rahbari, R., Mitchell, T. J., et al. (2020) · Nature · doi:10.1038/s41586-020-2214-z · Cited by 499 · see citing works
Genome-wide analysis of noncoding regulatory mutations in cancer
Weinhold, N., Jacobsen, A., Schultz, N., Sander, C., & Lee, W. (2014) · Nature Genetics · doi:10.1038/ng.3101 · Cited by 484 · see citing works
Suda, K., Nakaoka, H., Yoshihara, K., Ishiguro, T., Tamura, R., Mori, Y., Yamawaki, K., Adachi, S., Takahashi, T., Kase, H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.037 · Cited by 414 · see citing works
Extensive heterogeneity in somatic mutation and selection in the human bladder
Lawson, A. R. J., Abascal, F., Coorens, T. H. H., Hooks, Y., O’Neill, L., Latimer, C., Raine, K., Sanders, M. A., Warren, A. Y., Mahbubani, K. T. A., et al. (2020) · Science · doi:10.1126/science.aba8347 · Cited by 311 · see citing works
McDonald, S. A. C., Greaves, L. C., Gutierrez–Gonzalez, L., Rodriguez–Justo, M., Deheragoda, M., Leedham, S. J., Taylor, R. W., Lee, C. Y., Preston, S. L., Lovell, M., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2007.11.035 · Cited by 242 · see citing works
Macroscopic somatic clonal expansion in morphologically normal human urothelium
Li, R., Du, Y., Chen, Z., Xu, D., Lin, T., Jin, S., Wang, G., Liu, Z., Lu, M., Chen, X., et al. (2020) · Science · doi:10.1126/science.aba7300 · Cited by 206 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Clonal hematopoiesis: Mutation-specific adaptation to environmental change
Florez, M. A., Tran, B. T., Wathan, T. K., DeGregori, J., Pietras, E. M., & King, K. Y. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.05.006 · Cited by 129 · see citing works
Evolution of Multiple Myeloma from a Genomic Perspective
Maura, F., Samur, M., & Munshi, N. (2026) · Blood · doi:10.1182/blood.2024026313 · Cited by 8 · see citing works
Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion
Mannino, G., Quinn, G., Zhu, M., Wang, Z., Wang, X., Li, B., Hsieh, M.-H., Mathews, T., Zacharias, L., Gu, W., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci191855 · Cited by 4 · see citing works
- Authors
- Kakiuchi, N., & Ogawa, S.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Ogawa, Seishi
- Venue
- Nature Reviews Cancer
- Published
- 2021-02-24
- Volume
- 21
- Issue
- 4
- Pages
- 239-256
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W3132294763
- Cited by
- 252
- References
- 35
- Citations by year
- 2026: 38 · 2025: 52 · 2024: 42 · 2023: 43 · 2022: 52 · 2021: 25
- FWCI
- 4.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (20K21543, 20H03513, 19H05656)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- clonal expansion, driver mutations, cancer driver genes, aging, chronic inflammation, carcinogenesis, tissue remodeling, clonal evolution, environmental insults
- MeSH terms
- Clonal Hematopoiesis, Aging, Anemia, Aplastic, Barrett Esophagus, Bronchi, Clone Cells, Colitis, Ulcerative, Colon, Endometrium, Esophagus, Female, Gastric Mucosa, Humans, Inflammation, Liver, Liver Cirrhosis, Male, Metaplasia, Mutation, Neoplasms, Oncogenes, Skin, Stomach, Urothelium, Cell Proliferation, Clonal Evolution, Carcinogenesis
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
