Problems and paradigms Problems of somatic mutation and cancer Steven A. Frank* and Martin A. Nowak Summary releasing constraints on cellular reproduction (tumor sup- Somatic mutation plays a key role in transforming normal pressor genes). The great importance of mutation in cancer cells into cancerous cells. The analysis of cancer pro- progression justifies special attention to the nature of somatic gression therefore requires the study of how point mutations and chromosomal mutations accumulate in mutation. cellular lineages. The spread of somatic mutations We focus on the rate processes that govern the accumu- depends on the mutation rate, the number of cell divi- lation of somatic mutations. Key rate processes include the sions in the history of a cellular lineage, and the nature origin of somatic mutations, the accumulation of mutations of competition between different cellular lineages. We in cellular lineages, and the spread of mutated cell lines in consider how various aspects of tissue architecture and cellular competition affect the pace of mutation accu- competition with other cellular lineages. Prevention of cancer mulation. We also discuss the rise and fall of somatic largely means control of the rate at which cellular lineages mutation rates during cancer progression. BioEssays accumulate mutations. Through the study of rate processes, 26:291–299, 2004. ß 2004 Wiley Periodicals, Inc. one can begin to understand how different tissue architectures affect cancer progression and how mutation rates translate Introduction into rates of progression. It has often been noted that cancer arises from a Darwinian process of mutation and selection among somatic cells. But there is a unique aspect of cancer as an evolutionary system The primacy of somatic mutation that has not been emphasized. Many cellular genes function in cancer progression primarily to repress the competitive success of their bearers. Somatic mutation is not the only process that influences (4,5) Although natural selection can sometimes favor self-re- progression to cancer. Changes in the immune system, (6,8) (7) straint,(1,2) the unusual aspect of cells comes from the great hormonal status, gene expression, and signalling (9) number of cellular genes that enforce reproductive prudence. between tissues may affect the probability and the timing Such prudence arose as a necessary component of multi- of cancer progression. But somatic mutation is the only pro- cellularity.(1,3) cess that seems to play a key role in the progression of all Because selection at the organismal level favors re- tissues at all ages—it is the process, we believe, that explains strained cellular reproduction, many genes are tuned to keep most of the variation in age of cancer incidence. rates of cellular reproduction far below their potential. Somatic Perhaps the clearest evidence for the primacy of somatic (10–12) point mutations and chromosomal mutations can therefore mutation comes from germline mutations and from more easily increase cellular division or decrease cellular laboratory models with mechanisms to induce somatic (13) death than could mutations improve birth and death rates in mutation in particular tissues. The additional mutations other evolutionary systems. Put another way, a much higher almost invariably shorten the progression to cancer, and often proportion of mutations will be advantageous at the cellular do so in ways that can be easily understood. The conclusion level than at the organismal level. Somatic mutations that from this is clear: mutations have a powerful effect on the enhance cellular competitiveness may act directly by speeding kinetics of progression. Simple calculations suggest that the rate of cellular reproduction (oncogenes) or indirectly by somatic mutation occurs often enough to be a pervasive force.(14,15) Many other factors also influence the details of progression Funding agencies: National Science Foundation grant DEB–0089741 in particular cases. But it is a mistake to assume that the and National Institutes of Health grant AI24424 (SAF) and The existence of such additional factors means that they must be Packard Foundation and Jeffrey Epstein (MAN). as important as mutation for explaining the variation between *Correspondence to: Steven Frank, Department of Ecology & individuals in the quantitative timing of progression. If one is Evolutionary Biology, University of California, Irvine CA 92697, USA. interested in the details of why a particular tumor forms in E-mail: [email protected] DOI 10.1002/bies.20000 a particular place at a particular time, then those details Published online in Wiley InterScience (www.interscience.wiley.com). dominate. We are interested in the most important factors that affect the overall variation in the kinetics of progression in all BioEssays 26:291–299, ß 2004 Wiley Periodicals, Inc. BioEssays 26.3 291 Problems and paradigms tissues. The evidence strongly supports focus on mutation as If the same stem lineages continue to divide with increasing one of the key factors—perhaps the dominant factor in setting age, then epithelial stem lineages may divide many times. rate-limiting steps in progression. At age 60, an individual has lived about 22,000 days. Let us conservatively estimate human intestine renewal as every How does the architecture of renewing 7 days. Thus, people at age 60 have renewed their intestinal epithelial tissues affect the accumulation epithelium over 3,000 times. If we measure the age of cells as of mutations? the number of divisions in their somatic history, then some Epidermal and intestinal tissue are composed of many small stem cells in epithelial compartments may have divided 3,000 compartments, each compartment with no more than a few times by age 60. hundred to a few thousand cells.(16–20) The cells in different If we suppose that the mutation rate per gene per cell compartments divide independently and renew lost surface division is about 10À7, and there are about 105 genes, then the cells, with little mixing of cells between compartments. Tissue mutation rate per cell division in the coding region of the renewal occurs continuously. For example, the human intes- genome is about 10À2. The average stem lineage after 3,000 tine replaces its surface cells every few days. divisions would have experienced about 30 mutational events. Cairns(21) suggested that renewing tissues may reduce There are roughly 107 compartments in the colon and many the risk of cancer by separating into long-lived stem cells and also in the skin. With so many stem lineages, a large number short-lived transit cells. Stem cells divide repeatedly and of those lineages would experience hundreds of mutations by remain at the base of the epithelial compartments. Normally, the later stages of life. each stem cell division gives rise to one stem cell that remains These calculations suggest that some other process likely at the basal layer and one transit cell. The transit cell divides controls the accumulation of mutations. Cairns(21,26) argued a limited number of times, producing cells that move up from that stem cells may have reduced mutation rates compared the basal layer and eventually slough off from the surface. with other somatic cells. Two processes may reduce mutation For example, recent studies of human epidermal tissue rates. First, in each asymmetric stem cell division, the suggest that the skin renews from relatively slowly dividing stem lineage may retain the original DNA templates, with all basal stem cells that give rise to rapidly dividing transit new DNA copies segregating to the transit lineage. If most lineages, each transit lineage undergoing three to five rounds mutations occur in the production of new DNA strands, then of replication before sloughing from the surface.(19) Studies of most mutations would segregate to the transit lineage, and gastrointestinal compartments estimate four to six rounds of the stem lineage would accumulate fewer mutations per cell division by transit lineages.(22) division.(27,28) Second, stem cells may be particularly prone to The stem lineage renews the compartment and survives apoptosis in response to DNA damage, killing themselves over time. Thus, accumulation of somatic mutations occurs rather than risking repair of damage.(22,29) mainly in the stem lineage. Mutations in transit cells or differ- If these processes reduce stem cell mutation rates, then entiated cells may sometimes contribute to tumorigenesis but, carcinogens or other accidents that kill stem cells may have a in this paper, we focus on what we believe to be the dominant large effect on the accumulation of mutations in compart- rate-limiting steps, which probably occur most often in stem ments.(26) In particular, lost stem cells must be replaced by lineages. normal, symmetric cell division with typical mutation rates that Little is known about the history of stem lineages. For may be much higher than stem cell mutation rates. Thus, example, how many actively dividing stem cells renew a mutations may accumulate during periods in which stem cells compartment? This remains controversial. Potten’s group are being regenerated. estimated 4–6 active stem cells in each mouse intestinal compartment;(20) other estimates range from one stem cell to Is there a hierarchy of stem cells more than half of all cells in a compartment. to flush somatic mutations? With regard to the accumulation of mutations, a more The problem with a separation between stem cells and transit important issue concerns the lineage history of the active stem cells comes from the accumulation of mutations in long stem cells. Occasionally, a stem cell may die. The dead cell may be lineages. A hierarchy of stem cells could reduce the accu- replaced by the daughter of an active stem cell,(20) in which mulation of mutations.(30) We discuss two different mechan- case the total number of divisions in the history of stem isms, which we label stochastic flushing and deterministic lineages continues to increase over time.