Abstract
Cancer is driven by genomic mutations in ‘cancer driver’ genes, which have essential roles in tumor development. These mutations may be caused by exposure to mutagens in the environment or by endogenous DNA-replication errors in tissue stem cells. Recent observations of abundant mutations, including cancer driver mutations, in histologically normal human tissues suggest that mutations alone are not sufficient for tumor development, thus prompting the question of how single mutant cells give rise to neoplasia. In a concept supported by decades-old data from mouse tumor models, non-mutagenic tumor-promoting agents have been posited to activate the proliferation of dormant mutated cells, thus generating actively growing lesions, with the promotion stage as the rate-limiting step in tumor formation. Non-mutagenic promoting agents, either endogenous or environmental, may therefore have a more important role in human cancer etiology than previously thought.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H. & Vijg, J. Aging and genome maintenance: lessons from the mouse? Science 299, 1355–1359 (2003).
Odegard, V. H. & Schatz, D. G. Targeting of somatic hypermutation. Nat. Rev. Immunol. 6, 573–583 (2006).
Martincorena, I. et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).
Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).
Yokoyama, A. et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317 (2019).
Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019).
Brunner, S. F. et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature 574, 538–542 (2019).
Moore, L. et al. The mutational landscape of normal human endometrial epithelium. Nature 580, 640–646 (2020).
Suda, K. et al. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 24, 1777–1789 (2018).
Yoshida, K. et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature 578, 266–272 (2020).
Kim, S. K. et al. Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis. J. Gastroenterol. 54, 628–640 (2019).
Zhu, M. et al. Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease. Cell 177, 608–621.e12 (2019).
Nik-Zainal, S. & Hall, B. A. Cellular survival over genomic perfection. Science 366, 802–803 (2019).
Brown, K., Strathdee, D., Bryson, S., Lambie, W. & Balmain, A. The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted. Curr. Biol. 23, 516–24 (1998).
Yamagiwa, K. & Ichikawa, K. Über die künstliche Erzeugung von Papillom. Verh Jap Path Ges. 5, 142–148 (1915).
Berenblum, I. & Shubik, P. The role of croton oil applications, associated with a single painting of a carcinogen, in tumour induction of the mouse’s skin. Br. J. Cancer 1, 379–382 (1947).
Balmain, A. & Pragnell, I. B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature 303, 72–74 (1983).
Quintanilla, M., Brown, K., Ramsden, M. & Balmain, A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322, 78–80 (1986).
McCreery, M. Q. & Balmain, A. Chemical carcinogenesis models of cancer: back to the future. Annu. Rev. Cancer Biol. 1, 295–312 (2017).
Berenblum, I. & Shubik, P. The persistence of latent tumour cells induced in the mouse’s skin by a single application of 9:10-dimethyl-1:2-benzanthracene. Br. J. Cancer 3, 384–386 (1949).
Stenbäck, F., Peto, R. & Shubik, P. Initiation and promotion at different ages and doses in 2200 mice. Br. J. Cancer 44, 1–14 (1981).
Loehrke, H. et al. On the persistence of tumor initiation in two-stage carcinogenesis on mouse skin. Carcinogenesis 4, 771–775 (1983).
Goerttler, K., Loehrke, H., Schweizer, J. & Hesse, B. Two-stage skin carcinogenesis by systemic initiation of pregnant mice with 7,12-dimethylbenz(a)anthracene during gestation days 6-20 and postnatal promotion of the F 1-generation with the phorbol ester 12-tetradecanoylphorbol-13-acetate. J. Cancer Res. Clin. Oncol. 98, 267–275 (1980).
Goerttler, K., Loehrke, H., Hesse, B., Milz, A. & Schweizer, J. Diaplacental initiation of NMRI mice with 7,12-dimethylbenz[a]anthracene during gestation days 6–20 and postnatal treatment of the F1-generation with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate: tumor incidence in organs other than the skin. Carcinogenesis 2, 1087–1094 (1981).
McCreery, M. Q. et al. Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers. Nat. Med. 21, 1514–1520 (2015).
Nassar, D., Latil, M., Boeckx, B., Lambrechts, D. & Blanpain, C. Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma. Nat. Med. 21, 946–954 (2015).
Binder, R. L. et al. Squamous cell hyperplastic foci: precursors of cutaneous papillomas induced in SENCAR mice by a two-stage carcinogenesis regimen. Cancer Res. 58, 4314–4323 (1998).
Bauer, A. K., Dwyer-Nield, L. D., Keil, K., Koski, K. & Malkinson, A. M. Butylated hydroxytoluene (BHT) induction of pulmonary inflammation: a role in tumor promotion. Exp. Lung Res. 27, 197–216 (2001).
Snider, A. J. et al. Murine model for colitis-associated cancer of the colon. Methods Mol. Biol. 1438, 245–254 (2016).
Diwan, B. A., Rice, J. M. & Ward, J. M. Strain-dependent effects of phenobarbital on liver tumor promotion in inbred mice. Prog. Clin. Biol. Res. 331, 69–83 (1990).
Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).
Rapozo, D. C. M. et al. Recurrent acute thermal lesion induces esophageal hyperproliferative premalignant lesions in mice esophagus. Exp. Mol. Pathol. 100, 325–331 (2016).
Tomasetti, C. & Vogelstein, B. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015).
Wu, S., Powers, S., Zhu, W. & Hannun, Y. A. Substantial contribution of extrinsic risk factors to cancer development. Nature 529, 43–47 (2016).
Wild, C. et al. Cancer risk: role of chance overstated. Science 347, 728 (2015).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Schaal, C. & Chellappan, S. P. Nicotine-mediated cell proliferation and tumor progression in smoking-related cancers. Mol. Cancer Res. 12, 14–23 (2014).
Dérijard, B. et al. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76, 1025–1037 (1994).
Fu, T. et al. FXR regulates intestinal cancer stem cell proliferation. Cell 176, 1098–1112.e18 (2019).
Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).
Dolberg, D. S., Hollingsworth, R., Hertle, M. & Bissell, M. J. Wounding and its role in RSV-mediated tumor formation. Science 230, 676–678 (1985).
Weinberg, R. A. Oncogenes and the molecular basis of cancer. Harvey Lect. 80, 129–136 (1984). -1985–1985.
Murphy, G. et al. International cancer seminars: a focus on esophageal squamous cell carcinoma. Ann. Oncol. 28, 2086–2093 (2017).
Rose, Li,Y. et al. Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice. Nat. Commun. 11, 394 (2020).
Riva, L. et al. The mutational signature profile of known and suspected human carcinogens in mice. Nat. Genet. https://doi.org/10.1038/s41588-020-0692-4 (2020).
Salk, J. J., Schmitt, M. W. & Loeb, L. A. Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat. Rev. Genet. 19, 269–285 (2018).
Li, S., MacAlpine, D. M. & Counter, C. M. Capturing the primordial Kras mutation initiating urethane carcinogenesis. Nat. Commun. 11, 1800 (2020).
McMahon, C. M. et al. Clonal selection with Ras pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Cancer Discov. 9, 1050–1063 (2019).
Acknowledgements
This work was supported by a Cancer Research UK Grand Challenge Award (C98/A24032), US National Cancer Institute (NCI) grants R35CA210018 and UO1CA176287, and the Barbara Bass Bakar Professorship of Cancer Genetics (to A.B.). The author thanks numerous colleagues for discussions.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
A.B. is a member of the Scientific Advisory Board of Mission Bio, Inc. and has received funding support from Novartis and Bristol Myers Squibb.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Balmain, A. The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk. Nat Genet 52, 1139–1143 (2020). https://doi.org/10.1038/s41588-020-00727-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41588-020-00727-5
This article is cited by
-
NCAPD2 is a favorable predictor of prognostic and immunotherapeutic biomarker for multiple cancer types including lung cancer
Genes and Environment (2024)
-
Dissecting metastasis using preclinical models and methods
Nature Reviews Cancer (2023)
-
DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer
Nature Communications (2023)
-
Involvement and targeted intervention of benzo(a)pyrene-regulated apoptosis related proteome modification and muti-drug resistance in hepatocellular carcinoma
Cell Death & Disease (2023)
-
Peto’s paradox revisited: black box vs mechanistic approaches to understanding the roles of mutations and promoting factors in cancer
European Journal of Epidemiology (2023)