Cancer Etiology. Variation in Cancer Risk Among Tissues Can Be Explained by the Number of Stem Cell Divisions

Overview

Journal Science

Specialty Science

Date 2015 Jan 3

PMID 25554788

Citations 823

Authors

Cristian Tomasetti

Bert Vogelstein

Affiliations

Soon will be listed here.

Abstract

Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.

Citing Articles

The complex interplay between aging and cancer.

Trastus L, dAdda di Fagagna F Nat Aging. 2025; .

PMID: 40038418 DOI: 10.1038/s43587-025-00827-z.

EpCAM Signaling in Oral Cancer Stem Cells: Implications for Metastasis, Tumorigenicity, and Therapeutic Strategies.

Chang C, Tsai C, Tsai F, Chu T, Hsu P, Kuo C Curr Issues Mol Biol. 2025; 47(2).

PMID: 39996844 PMC: 11854592. DOI: 10.3390/cimb47020123.

Recent research progress on metal ions and metal-based nanomaterials in tumor therapy.

Xu Y, Reheman A, Feng W Front Bioeng Biotechnol. 2025; 13:1550089.

PMID: 39991139 PMC: 11842396. DOI: 10.3389/fbioe.2025.1550089.

Genetic regulation of TERT splicing affects cancer risk by altering cellular longevity and replicative potential.

Florez-Vargas O, Ho M, Hogshead M, Papenberg B, Lee C, Forsythe K Nat Commun. 2025; 16(1):1676.

PMID: 39956830 PMC: 11830802. DOI: 10.1038/s41467-025-56947-y.

Cancer can be a purely epigenetic disorder.

Meng Y, Sun H, Deng C Int J Biol Sci. 2025; 21(3):955-957.

PMID: 39897047 PMC: 11781178. DOI: 10.7150/ijbs.109274.

References

Albanes D, Winick M . Are cell number and cell proliferation risk factors for cancer?. J Natl Cancer Inst. 1988; 80(10):772-4. DOI: 10.1093/jnci/80.10.772. View

Colditz G, Wolin K, Gehlert S . Applying what we know to accelerate cancer prevention. Sci Transl Med. 2012; 4(127):127rv4. PMC: 3343638. DOI: 10.1126/scitranslmed.3003218. View

Knudson Jr A . Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971; 68(4):820-3. PMC: 389051. DOI: 10.1073/pnas.68.4.820. View

Dubal P, Svider P, Kanumuri V, Patel A, Baredes S, Eloy J . Laryngeal chondrosarcoma: a population-based analysis. Laryngoscope. 2014; 124(8):1877-81. DOI: 10.1002/lary.24618. View

Stratton M, Campbell P, Futreal P . The cancer genome. Nature. 2009; 458(7239):719-24. PMC: 2821689. DOI: 10.1038/nature07943. View

Baker S, Cappuccio A, Potter J . Research on early-stage carcinogenesis: are we approaching paradigm instability?. J Clin Oncol. 2010; 28(20):3215-8. PMC: 2903322. DOI: 10.1200/JCO.2010.28.5460. View

Garraway L, Lander E . Lessons from the cancer genome. Cell. 2013; 153(1):17-37. DOI: 10.1016/j.cell.2013.03.002. View

Reya T, Morrison S, Clarke M, Weissman I . Stem cells, cancer, and cancer stem cells. Nature. 2001; 414(6859):105-11. DOI: 10.1038/35102167. View

Kandoth C, McLellan M, Vandin F, Ye K, Niu B, Lu C . Mutational landscape and significance across 12 major cancer types. Nature. 2013; 502(7471):333-339. PMC: 3927368. DOI: 10.1038/nature12634. View

10.

Blanpain C, Fuchs E . Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol. 2009; 10(3):207-17. PMC: 2760218. DOI: 10.1038/nrm2636. View

11.

Fearon E . Human cancer syndromes: clues to the origin and nature of cancer. Science. 1997; 278(5340):1043-50. DOI: 10.1126/science.278.5340.1043. View

12.

Booth C, Potten C . Gut instincts: thoughts on intestinal epithelial stem cells. J Clin Invest. 2000; 105(11):1493-9. PMC: 300863. DOI: 10.1172/JCI10229. View

13.

Ward J, Uno H, Kurata Y, Weghorst C, Jang J . Cell proliferation not associated with carcinogenesis in rodents and humans. Environ Health Perspect. 1993; 101 Suppl 5:125-35. PMC: 1519455. DOI: 10.1289/ehp.93101s5125. View

14.

Snippert H, van der Flier L, Sato T, van Es J, van den Born M, Kroon-Veenboer C . Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell. 2010; 143(1):134-44. DOI: 10.1016/j.cell.2010.09.016. View

15.

Danaei G, Vander Hoorn S, Lopez A, Murray C, Ezzati M . Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet. 2005; 366(9499):1784-93. DOI: 10.1016/S0140-6736(05)67725-2. View

16.

Tomasetti C, Vogelstein B, Parmigiani G . Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. Proc Natl Acad Sci U S A. 2013; 110(6):1999-2004. PMC: 3568331. DOI: 10.1073/pnas.1221068110. View

17.

Vogelstein B, Papadopoulos N, Velculescu V, Zhou S, Diaz Jr L, Kinzler K . Cancer genome landscapes. Science. 2013; 339(6127):1546-58. PMC: 3749880. DOI: 10.1126/science.1235122. View

18.

Lichtenstein P, Holm N, Verkasalo P, Iliadou A, Kaprio J, Koskenvuo M . Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000; 343(2):78-85. DOI: 10.1056/NEJM200007133430201. View

19.

Armitage P, DOLL R . A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br J Cancer. 1957; 11(2):161-9. PMC: 2073730. DOI: 10.1038/bjc.1957.22. View

20.

Sell S . Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?. Environ Health Perspect. 1993; 101 Suppl 5:15-26. PMC: 1519468. DOI: 10.1289/ehp.93101s515. View