Variation in cancer risk between organs can not be explained by the degree of somatic clonal expansion

Abstract

Somatic clonal expansion refers to the proliferation and expansion of a cell clone within a multicellular organism. Since cancer also results from the uncontrolled proliferation of few cell clones, it is generally believed that aging-associated somatic clonal expansion observed in normal tissues represents a precancerous condition. For instance, hematological malignancy is often preceded by clonal hematopoiesis. However, the precise connection between cancer and somatic clonal expansion remains elusive in solid organs. In this study, we utilized a straightforward method to assess the relative quantitative degrees of clonal expansion in nine human organs. Our findings reveal that the degree of clonal expansion varies across different organs while remaining consistent among different individuals. Contrary to the general belief, we did not identify any significant correlation between lifetime cancer risk and the degree of lifetime somatic clonal expansion. For example, the lifetime risk of colorectal cancer is approximately 20 times higher than that of esophageal cancer, yet the former exhibited the lower degree of clonal expansion than the latter. Our results suggest that somatic clonal expansion represents an evolutionary process distinct from carcinogenesis in normal tissues, providing novel perspectives on precancerous conditions.

Keywords

Somatic mutations / Allele frequency spectrum / Clonal expansion / Lifetime cancer risk

References

[] Abby E, Dentro SC, Hall MWJ, Fowler JC, Ong SH, Sood R, Herms A, et al.. Notch1 Mutations Drive Clonal Expansion in Normal Esophageal Epithelium but Impair Tumor Growth. Nat Genet, 2023, 55(2): 232-245, pmcid: 9925379

[] Acha-Sagredo A, Ganguli P, Ciccarelli FD. Somatic Variation in Normal Tissues: Friend or Foe of Cancer Early Detection?. Ann Oncol, 2022, 33(12): 1239-1249,

[] Armitage P, Doll R. The Age Distribution of Cancer and a Multi-Stage Theory of Carcinogenesis. Br J Cancer, 1954, 8(1): 1-12, pmcid: 2007940

[] Brunner SF, Roberts ND, Wylie LA, Moore L, Aitken SJ, Davies SE, Sanders MA, et al.. Somatic Mutations and Clonal Dynamics in Healthy and Cirrhotic Human Liver. Nature, 2019, 574(7779): 538-542, pmcid: 6837891

[] Chan HT, Chin YM, Nakamura Y, Low S-K. Clonal Hematopoiesis in Liquid Biopsy: From Biological Noise to Valuable Clinical Implications. Cancers, 2020, 12(8): 2277, pmcid: 7463455

[] Fabre MA, Guilherme J, de Almeida E, Fiorillo EM, Damaskou A, Rak J, Orrù V, et al.. The Longitudinal Dynamics and Natural History of Clonal Haematopoiesis. Nature, 2022, 606(7913): 335-342, pmcid: 9177423

[] Fearon ER, Vogelstein B. A Genetic Model for Colorectal Tumorigenesis. Cell, 1990, 61(5): 759-767,

[] Fisher JC. Multiple-Mutation Theory of Carcinogenesis. Nature, 1958, 181(4609): 651-652,

[] Idalsoaga, Francisco, Anand V. Kulkarni, Omar Y. Mousa, Marco Arrese, and Juan Pablo Arab. 2020. “Non-Alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease: Two Intertwined Entities.” Frontiers in Medicine 7. https://www.frontiersin.org/articles/https://doi.org/10.3389/fmed.2020.00448 (July 4, 2023).

[] Jonason AS, Kunala S, Price GJ, Restifo RJ, Spinelli HM, Persing JA, Leffell DJ, Tarone RE, Brash DE. Frequent Clones of P53-Mutated Keratinocytes in Normal Human Skin. Proc Natl Acad Sci, 1996, 93(24): 14025-14029, pmcid: 19488

[] Knudson AG. Mutation and Cancer: Statistical Study of Retinoblastoma. Proc Natl Acad Sci, 1971, 68(4): 820-823, pmcid: 389051

[] Lawson ARJ, Abascal F, Coorens THH, Hooks Y, O’Neill L, Latimer C, Raine K, et al.. Extensive Heterogeneity in Somatic Mutation and Selection in the Human Bladder. Science, 2020, 370(6512): 75-82,

[] Lee-Six H, Øbro NF, Shepherd MS, Grossmann S, Dawson K, Belmonte M, Osborne RJ, et al.. Population Dynamics of Normal Human Blood Inferred from Somatic Mutations. Nature, 2018, 561(7724): 473-478, pmcid: 6163040

[] Lee-Six H, Olafsson S, Ellis P, Osborne RJ, Sanders MA, Moore L, Georgakopoulos N, et al.. The Landscape of Somatic Mutation in Normal Colorectal Epithelial Cells. Nature, 2019, 574(7779): 532-537,

[] Li R, Di L, Li J, Fan W, Liu Y, Guo W, Liu W, et al.. A Body Map of Somatic Mutagenesis in Morphologically Normal Human Tissues. Nature, 2021, 597(7876): 398-403,

[] Manders, Freek, Ruben van Boxtel, and Sjors Middelkamp. 2021. “The Dynamics of Somatic Mutagenesis During Life in Humans.”Frontiers in Aging2. https://www.frontiersin.org/articles/https://doi.org/10.3389/fragi.2021.802407 (March 13, 2023).

[] Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, Wedge DC, et al.. High Burden and Pervasive Positive Selection of Somatic Mutations in Normal Human Skin. Science, 2015, 348(6237): 880-886, pmcid: 4471149

[] Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F, Hall MWJ, Cagan A, et al.. Somatic Mutant Clones Colonize the Human Esophagus with Age. Science, 2018, 362(6417): 911-917, pmcid: 6298579

[] McKerrell T, Park N, Moreno T, Grove CS, Ponstingl H, Stephens J, Crawley C, et al.. Leukemia-Associated Somatic Mutations Drive Distinct Patterns of Age-Related Clonal Hemopoiesis. Cell Rep, 2015, 10(8): 1239-1245, pmcid: 4542313

[] Mitchell SR, Gopakumar J, Jaiswal S. Insights into Clonal Hematopoiesis and Its Relation to Cancer Risk. Curr Opin Genet Dev, 2021, 66: 63-69, pmcid: 8388615

[] Mitchell E, Chapman MS, Williams N, Dawson KJ, Mende N, Calderbank EF, Jung H, et al.. Clonal Dynamics of Haematopoiesis across the Human Lifespan. Nature, 2022, 606(7913): 343-350, pmcid: 9177428

[] Moolgavkar, Suresh H., and Alfred G. Knudson. 1981. “Mutation and Cancer: A Model for Human Carcinogenesis.” J Nat Cancer Inst. 66(6): 1037–52. doi:https://doi.org/10.1093/jnci/66.6.1037.

[] Moore L, Cagan A, Coorens THH, Neville MDC, Sanghvi R, Sanders MA, Oliver TRW, et al.. The Mutational Landscape of Human Somatic and Germline Cells. Nature, 2021, 597(7876): 381-386,

[] Nordling CO. A New Theory on the Cancer-Inducing Mechanism. Br J Cancer, 1953, 7(1): 68-72, pmcid: 2007872

[] Sharma, Bashar, and Savio John. 2023. “Hepatic Cirrhosis.” In StatPearls, Treasure Island (FL): StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK482419/ (September 11, 2023).

[] Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Tamura R, Mori Y, Yamawaki K, et al.. Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium. Cell Rep, 2018, 24(7): 1777-1789,

[] Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, Boutselakis H, et al.. COSMIC: The Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res, 2019, 47(D1): D941-D947,

[] Tomasetti C, Vogelstein B. Variation in Cancer Risk among Tissues Can Be Explained by the Number of Stem Cell Divisions. Science, 2015, 347(6217): 78-81, pmcid: 4446723

[] Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer Genome Landscapes. Science, 2013, 339(6127): 1546-1558, pmcid: 3749880

[] Xie M, Charles Lu, Wang J, McLellan MD, Johnson KJ, Wendl MC, McMichael JF, et al.. Age-Related Mutations Associated with Clonal Hematopoietic Expansion and Malignancies. Nat Med, 2014, 20(12): 1472-1478, pmcid: 4313872

[] Yokoyama A, Kakiuchi N, Yoshizato T, Nannya Y, Suzuki H, Takeuchi Y, Shiozawa Y, et al.. Age-Related Remodelling of Oesophageal Epithelia by Mutated Cancer Drivers. Nature, 2019, 565(7739): 312-317,

[] Yoshida K, Gowers KHC, Lee-Six H, Chandrasekharan DP, Coorens T, Maughan EF, Beal K, et al.. Tobacco Smoking and Somatic Mutations in Human Bronchial Epithelium. Nature, 2020, 578(7794): 266-272, pmcid: 7021511

[] Zhu M, Tianshi Lu, Jia Y, Luo X, Gopal P, Li L, Odewole M, et al.. Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease. Cell, 2019, 177(3): 608-621.e12, pmcid: 6519461

Funding

the National Key R&D Program of China(2021YFA1302501); the National Natural Science Foundation of China(32200492)