Skip to main content
  • Facebook
  • Twitter
  • YouTube
  • LinkedIn
  • Google Plus
  • Other GSA Resources
    • Genetics Society of America
    • G3: Genes | Genomes | Genetics
    • Genes to Genomes: The GSA Blog
    • GSA Conferences
    • GeneticsCareers.org
  • Log in
Genetics

Main menu

  • HOME
  • ISSUES
    • Current Issue
    • Early Online
    • Archive
  • ABOUT
    • About the journal
    • Why publish with us?
    • Editorial board
    • Early Career Reviewers
    • Contact us
  • SERIES
    • Centennial
    • Genetics of Immunity
    • Genetics of Sex
    • Genomic Prediction
    • Multiparental Populations
    • FlyBook
    • WormBook
    • YeastBook
  • ARTICLE TYPES
    • About Article Types
    • Commentaries
    • Editorials
    • GSA Honors and Awards
    • Methods, Technology & Resources
    • Perspectives
    • Primers
    • Reviews
    • Toolbox Reviews
  • PUBLISH & REVIEW
    • Scope & publication policies
    • Submission & review process
    • Article types
    • Prepare your manuscript
    • Submit your manuscript
    • After acceptance
    • Guidelines for reviewers
  • SUBSCRIBE
    • Why subscribe?
    • For institutions
    • For individuals
    • Email alerts
    • RSS feeds
  • Other GSA Resources
    • Genetics Society of America
    • G3: Genes | Genomes | Genetics
    • Genes to Genomes: The GSA Blog
    • GSA Conferences
    • GeneticsCareers.org

User menu

Search

  • Advanced search
Genetics

Advanced Search

  • HOME
  • ISSUES
    • Current Issue
    • Early Online
    • Archive
  • ABOUT
    • About the journal
    • Why publish with us?
    • Editorial board
    • Early Career Reviewers
    • Contact us
  • SERIES
    • Centennial
    • Genetics of Immunity
    • Genetics of Sex
    • Genomic Prediction
    • Multiparental Populations
    • FlyBook
    • WormBook
    • YeastBook
  • ARTICLE TYPES
    • About Article Types
    • Commentaries
    • Editorials
    • GSA Honors and Awards
    • Methods, Technology & Resources
    • Perspectives
    • Primers
    • Reviews
    • Toolbox Reviews
  • PUBLISH & REVIEW
    • Scope & publication policies
    • Submission & review process
    • Article types
    • Prepare your manuscript
    • Submit your manuscript
    • After acceptance
    • Guidelines for reviewers
  • SUBSCRIBE
    • Why subscribe?
    • For institutions
    • For individuals
    • Email alerts
    • RSS feeds
Previous ArticleNext Article

Cancer and the Immortal Strand Hypothesis

John Cairns
Genetics November 1, 2006 vol. 174 no. 3 1069-1072; https://doi.org/10.1534/genetics.104.66886
John Cairns
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
Loading

Anecdotal, Historical and Critical Commentaries on Genetics

Edited by James F. Crow and William F. Dove

THE main causes of mortality in the Western world are largely a matter of somatic genetics. As we age, our cells accumulate more and more mutations. Eventually one of them acquires a set of changes in phenotype that allows it to generate an expanding clone of descendants, causing an atheromatous plaque in an artery or an invasive cancer. These changes are the result of a cumulative process extending throughout our life, as is demonstrated in the relation between smoking and lung cancer and between pregnancy and breast cancer. Someone who started smoking at the age of 15 will, when 65, have a higher risk of lung cancer than someone who started at 20, showing that lungs can store for half a century the damage acquired in your teenage years (Doll and Peto 1981). Conversely, because pregnancy protects somewhat against the subsequent risk of breast cancer, a woman who first became pregnant when 13 will, when 70, have a lower risk of breast cancer than a woman whose first pregnancy was in her 20s, showing that the latter was accumulating risk as a teenager (MacMahon et al. 1973).

Long-lived animals protect themselves from the physical and chemical dangers of their environment by continuous replacement of the cells on their external surfaces and it is in these sites of continuous cell division that most human cancers arise. An adult human contains ∼1012 rapidly multiplying cells. During a life span of ∼30,000 days, each of us makes and discards from skin, gut, and certain internal organs such as lymph glands and bone marrow about one-third of these cells each day (Potten and Morris 1988). If all these 1012 cells divide every third day, the cells remaining after 80 years would each have had ∼10,000 successive divisions in their ancestry. So by the age of 80, given a mutation rate of ∼10−6/gene/replication (Drake 1999), 1 in 100 of the copies of each gene would be mutant. In a collection of 1012 cells, 1010 would have a mutant copy of any particular gene, 108 would have mutations in any pair of genes, and a million would have mutations in any trio of genes. Nevertheless, despite there being many combinations of mutant genes that can trigger cancer (Hahn and Weinberg 2002), most people never develop cancer. So there must be some feature of multicellular systems that slows the rate of accumulation of replication errors.

PROTECTION BY THE CONTROL OF LINEAGE

In each region of a rapidly multiplying tissue there are a few long-lived “stem” cells, which periodically divide asymmetrically, with one of the daughter cells replacing its mother and with the other generating a clone that replaces the existing rapidly dividing population. The rate of accumulation of mutations in each tissue therefore reflects the properties of the tissue's stem cells. One obvious way to lower the rate of accumulation of errors of replication would therefore be to slow the rate of the division of stem cells. For example, consider a tissue in which the cycle time of the rapidly multiplying cells is one Nth of the animal's lifetime. If this were true for every cell in the tissue, any cell still present at the end of the animal's life would necessarily have had N divisions in its ancestry (ignoring the relatively small number of divisions initially needed to create the tissue). If, however, this population of cells is periodically completely replaced by a clone arising from an underlying slowly dividing stem cell and if that stem cell produces a replacing clone S times in the animal's life, then the greatest number of divisions that the fast-dividing cells in these clones can have is N/S, the number of divisions of the stem cells will be S, and at the end of the animal's life the maximum number of divisions in any cell's ancestry will be (S + N/S) (note that S and N reflect the frequency of division of the two classes of cell, not the number of such cells). The minimum value of (S + N/S) is Math and is reached when Math. For example, in the small intestine of a mouse the cycle time of the 1010 fast-dividing cells is ∼1/2000th of the usual maximum life span of a mouse (3 years), and therefore N = 2000. If the cells in each region of this epithelium were being replenished by the divisions of a single stem cell, that stem cell ideally should have divided Math (i.e., 45 times) during a mouse's life span, or roughly once every 3–4 weeks. Instead of the 1010 cells in this old mouse's small intestine having 2000 divisions in their ancestry, none could have >90 divisions in their ancestry (Math) and so there would be slightly less than one-twentieth as many mutant cells. And if there were a hierarchy of stem cells in a tissue, each with a slower rate of division than its stem cell daughters, the maximum number of divisions could be further reduced.

Some systems of proliferating cells are known to be periodically replenished from separate groups of cells that divide rarely if at all. For example, human hair follicles are totally replaced roughly every 3 years by a clone arising from a cell exported from a stationary population of cells in what is called the “bulge” region of the hair follicle (Cotsarelis et al. 1990). Similarly, the apical stem cells in the growing shoots of many plants are probably periodically replenished by a cell coming from the nearby “quiescent center” (Barlow 1976). But, in the best-studied epithelia, such as mouse epidermis and gut, the rate of division of the stem cells at the base of the epithelium is about one-half the rate of the fast-growing cells and there is no evidence for the existence of rarely dividing stem cells, let alone precisely ordered hierarchies of stem cells. Furthermore, it seems unlikely that precise hierarchies exist, because mutant frequencies have been observed to rise roughly linearly with age both in human lymphocytes and in mouse small intestine (Winton et al. 1988; Finette et al. 1994). Contrary to what one might have expected, therefore, the control of mutation rates in epithelia may not depend on a drastic reduction in the length of lineages achieved by a great reduction in the rate of division of stem cells. Yet the accumulation of mutations in epithelia is somehow slowed because most cancers arise only in old age, and this protection must be occurring in stem cells because they are the only epithelial cells that survive from one year to the next.

PROTECTION BY THE SEGREGATION OF MUTATIONS

Changes in DNA sequence arise from errors during replication or repair. But a change in sequence is not fixed irreversibly until it is present in both strands—i.e., has been copied at the next round of replication. It seemed possible, therefore, that stem cells might avoid accumulating mutations if, at mitosis, they always kept, for each chromosome, the chromatid with the older template strand (Cairns 1975). Bacteria were known to keep together the template strands of separate replicons (Cuzin and Jacob 1965) and this form of control has been observed in mouse embryonic cells in culture (Lark et al. 1966) and in the growing root tips of plants (Lark 1967) and perhaps in mouse tongue (Potten et al. 1978). Recently, studies of stem cells in the mouse small intestine (Potten et al. 2002), breast (Smith 2005), brain (Karpowicz et al. 2005), and muscle (Shinin et al. 2006) have shown that these stem cells do indeed keep the same parental DNA strands through successive divisions and, in one case, that their non-stem-cell daughters do not (Shinin et al. 2006). This arrangement ensures that any errors arising in stem cells during gene duplication avoid being permanently fixed because they are passed on, at the asymmetric division of each stem cell, to the differentiating daughter cell and will therefore soon be discarded.

The interactions of gene products underlying these properties of stem cells are not understood, but it seems likely that they involve the action of P53. Thus, when p53 in non-stem cells grown in vitro is continuously overexpressed, the cells behave like stem cells in that they keep their old template strands together (Merok et al. 2002). Furthermore, under these conditions, one of each pair of daughter cells is unable to divide again, suggesting that there is a strand-dependent P53-dependent checkpoint that forces one of the daughters to behave like a stem cell.

The preservation of “immortal strands” entails certain restraints on the types of DNA repair available to stem cells. Recombinational repair, for example, involves the interchange of new and old strands, and so if stem cells are to keep the same template strands through many divisions, they must avoid sister-chromatid exchange. It was therefore not surprising to learn that embryonic stem cells are deficient in certain kinds of repair (Roth and Samson 2002) and apparently cannot carry out mitotic recombination (Cervantes et al. 2002), which may be why they are extremely sensitive to certain kinds of DNA damage (Potten 1977).

The only DNA lesions (potential mutations) that persist in epithelia (i.e., accumulate over a lifetime) may be those that are fixed in a cell that later is promoted into being a stem cell. When a stem cell is killed (e.g., by radiation), it is replaced by the dedifferentiation of a differentiating daughter cell (Hendry et al. 1992). This may be why the frequency of mutation in epithelial stem cells during continuous mutagenesis increases as the square of time (Shaver-Walker et al. 1995); for, to put a mutation in a stem cell, first the existing stem cell must be killed and second its replacement must have become mutant in both strands (Cairns 2002).

What we see here, therefore, is a system that slows the accumulation of mutations. When stem cells are not being killed, they multiply slowly and may therefore have a long period in which to check their genome for errors, and whenever they are killed, they are replaced by transiently repair-proficient daughter cells. Another factor that saves epithelia from the selection of fitter mutants is their stem cells' dependence on signals coming from neighboring cells in the stem cell niche (Watt and Hogan 2000). For example, in human skin, mutant stem cells can produce aggressive clones of descendants that out-compete the daughters of neighboring nonmutant stem cells, but these clones usually cannot take over neighboring niches if there are stem cells in those niches (Zhang et al. 2001); similarly, mouse blood contains circulating stem cells that can repopulate marrow but only if the existing marrow stem cells have been killed (Micklem et al. 1975). Indeed, in the absence of continual cell damage, it seems that such expanded mutant clones tend to do less well than their normal neighbors. For example, skin tumors produced in rabbit ears by coal tar usually disappear when the skin is not being continually treated but duly reappear at the same place (presumably from the same mutant stem cells) when treatment is resumed (Mackenzie and Rous 1941). Those classical experiments in carcinogenesis showed how the natural selection of fitter variants is inhibited in the rapidly multiplying tissues of long-lived animals. There is, however, clear epidemiological and experimental evidence for yet another final, rate-limiting barrier to the development of many human cancers that apparently does not require either cell death or mutagenesis (Peto 2001).

THE FINAL, POSSIBLY EPIGENETIC, STEP IN CARCINOGENESIS

Once again we start with what is known about the timing of events in the creation of the commonest human cancers. The annual death rates from breast cancer and cervical cancer rise steeply up to middle age but remain almost constant for the next 10–20 years. As pointed out many years ago (Prehn 1977), it is as if creation of breast and cervical cancers (and certain experimental cancers) requires a final step that is of a different kind from the preceding steps. Prehn (1997) has suggested that the critical event is when a stem cell has to undergo symmetrical rather than its normally asymmetric mitosis. A slightly different interpretation now seems more likely. Several studies have shown that in ex-smokers the annual death rate from lung cancer remains for the next 20 years close to the level it had reached when the smoker quit smoking. This suggests that the last step is a rare event affecting existing mutant cells that, astonishingly, is not accelerated by smoking.

The main cause of lung cancer in smokers is presumably the continuing cell death and mutagenesis that occurs in lung epithelium exposed to the toxins and mutagens in burning tobacco. The main cause of breast cancer is less obvious; mammary epithelium is known to undergo periodic expansion and contraction during the period of accumulating risk (Masters et al. 1977), and it therefore seemed possible that the rising risk of both breast and cervical cancer in young women could be due to the accumulation of mutations associated with the repeated generation and loss of stem cells (Cairns 1975), helped in the case of cervical cancer by HPV infection, which inactivates the p53- and Rb1-dependent mechanism for recognizing DNA damage. However, the example of lung cancer in ex-smokers adds a totally unexpected element.

At any moment, the frequency of any class of cancer presumably reflects the number of cells that have undergone all but the final step in carcinogenesis, multiplied by the rate of whatever happens to be the final step. If this final step required DNA damage, the death rate from lung cancer would quickly drop when the mutagenic stimulus (smoking) was removed. In fact, as already mentioned, at that point the death rate shows no decline and for the next 10–20 years actually stays roughly at the level it had reached in the year before the smoker stopped smoking (Halpern et al. 1993). This suggests that the final step, which starts the growth of three common human cancers (cancer of the lung, breast, and cervix), is an event of a different kind from the steps that lead to the accumulation of mutant cells because, unlike the earlier steps, it does not have to be stimulated by the toxicity and mutagenicity of tobacco or by the ebb and flow of mammary and cervical epithelium, but occurs at a constant rate. It must, however, be a rare event because the incidence of lung cancer in ex-smokers, even in those who smoked for >40 years, is <1% a year.

The final step in carcinogenesis initiates the growth of a presumably fully mutant stem cell, creating a perpetually expanding cancerous clone in which more mutations will inevitably arise. We have to ask what kind of rare event can alter the fate of stem cells and of their immediate descendants. Normally, each time a stem cell divides, its two daughters have different fates: one has to replace its parent and stay within the confines of the stem cell niche, while the other is programmed to differentiate and multiply and eventually all its descendants die and are discarded. The final step could be the rare failure of this dichotomy, when a fully mutant cancerous stem cell produces a daughter cell that is freed from some nongenetic imperative to differentiate and die (an event analogous to Prehn's “symmetrical division”). The most important feature and perhaps the evolutionary origin of the preservation of immortal strands may have been that it provided the basis for a strand-based epigenetic mechanism that distinguished daughter cells from their mothers and, later in evolution, could not only determine the phenotypes of the cells in the different tissues of multicellular organisms but also distinguish the stem cells in those tissues from their differentiating daughters.

Acknowledgments

I am indebted to Julian Peto, who explained to me the significance of the incidence of lung cancer in ex-smokers, and to Richard Peto and Rory Collins for the hospitality of the Clinical Trial Service Unit.

  • Copyright © 2006 by the Genetics Society of America

References

  1. ↵
    Barlow, P. W., 1976 The concept of the stem cell in the context of plant growth and development. J. Theor. Biol. 57: 433–451.
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    Cairns, J., 1975 Mutation, selection and cancer. Nature 255: 197–200.
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    Cairns, J., 2002 Somatic stem cells and the kinetics of mutagenesis and carcinogenesis. Proc. Natl. Acad. Sci. USA 99: 10567–10570.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Cervantes, R. B., J. R. Stringer, C. Shao, J. A. Tischfield and P. J. Stambrook, 2002 Embryonic stem cells and somatic cells differ in mutation frequency and type. Proc. Natl. Acad. Sci. USA 99: 3586–3590.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Cotsarelis, G., T. T. Sun and R. M. Lavker, 1990 Label-retaining cells reside in the bulge area of pilosebacious unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61: 1329–1337.
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    Cuzin, F., and F. Jacob, 1965 Existence chez Escherichia coli d'une unité gènétique de ségrégation formée de différents réplicons. C. R. Acad. Sci. Paris 260: 5411–5414.
    OpenUrl
  7. ↵
    Doll, R., and R. Peto, 1981 The Causes of Cancer. Oxford University Press.
  8. ↵
    Drake, J. W., 1999 The distribution of rates of spontaneous mutation over viruses, prokaryotes, and eukaryotes. Ann. NY Acad. Sci. 870: 100–107.
    OpenUrlCrossRefPubMedWeb of Science
  9. ↵
    Finette, B. A., L. M. Sullivan, J. P. O'Neill, J. A. Nicklas, P. M. Vacek et al., 1994 Determination of hprt mutant frequencies in T-lymphocytes from a healthy pediatric population: statistical comparison between new-born, children and adult mutant frequencies, clonal efficiency and age. Mutat. Res. 308: 223–231.
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    Hahn, W. C., and R. A. Weinberg, 2002 Rules for making human tumor cells. New Engl. J. Med. 347: 1593–1603.
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    Halpern, M. T., B. W. Gillespie and K. E. Warner, 1993 Patterns of absolute risk of lung cancer mortality in former smokers. J. Natl. Cancer Inst. 85: 457–464.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Hendry, J. H., S. A. Roberts and C. S. Potten, 1992 The clonogenic content of murine intestinal crypts: dependence on radiation dose used in its determination. Radiat. Res. 132: 115–119.
    OpenUrlPubMedWeb of Science
  13. ↵
    Karpowicz, P., C. Morshead, A. Kam, E. Jervis, J. Ramuns et al., 2005 Support for the immortal strand hypothesis: neural stem cells partition DNA strands asymmetrically in vitro. J. Cell Biol. 170: 721–732.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Lark, K. G., 1967 Non-Mendelian segregation of sister chromatids in Vicia faba and Triticum boeoticum. Proc. Natl. Acad. Sci. USA 58: 352–359.
    OpenUrlFREE Full Text
  15. ↵
    Lark, K. G., R. A. Consigli and H. C. Minocha, 1966 Segregation of sister chromatids in mammalian cells. Science 154: 1202–1205.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Mackenzie, I., and P. Rous, 1941 The experimental disclosure of latent neoplastic changes in tarred skin. J. Exp. Med. 73: 391–416.
    OpenUrlAbstract
  17. ↵
    MacMahon, B., P. Cole and J. Brown, 1973 Etiology of human breast cancer: a review. J. Natl. Cancer Inst. 50: 21–42.
    OpenUrlPubMedWeb of Science
  18. ↵
    Masters, J. R. W., J. O. Drife and J. J. Scarisbrick, 1977 Cyclic variation of DNA synthesis in human breast epithelium. J. Natl. Cancer Inst. 58: 1263–1265.
    OpenUrlPubMedWeb of Science
  19. ↵
    Merok, J. R., J. A. Lansita, J. R. Tunstead and J. L. Sherley, 2002 Cosegregation of chromosomes containing immortal DNA strands in cells that cycle with asymmetric stem cell kinetics. Cancer Res. 62: 6791–6795.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Micklem, H. S., C. E. Ford, E. P. Evans and D. A. Ogden, 1975 Compartments and cell flows within the mouse haemopoietic system. 1. Restricted interchange between haemopoietic sites. Cell Tissue Kinet. 8: 219–232.
    OpenUrlPubMedWeb of Science
  21. ↵
    Peto, J., 2001 Cancer epidemiology in the last century and the next decade. Nature 411: 390–395.
    OpenUrlCrossRefPubMed
  22. ↵
    Potten, C. S., 1977 Extreme sensitivity of some intestinal crypt cells to X and γ irradiation. Nature 269: 518–521.
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    Potten, C. S., and R. J. Morris, 1988 Epithelial stem cells in vivo. J. Cell Sci. 10(Suppl.): 45–62.
    OpenUrlPubMed
  24. ↵
    Potten, C. S., W. J. Hume, P. Reid and J. Cairns, 1978 The segregation of DNA in epithelial stem cells. Cell 15: 899–906.
    OpenUrlCrossRefPubMedWeb of Science
  25. ↵
    Potten, C. S., G. Owen and D. Booth, 2002 Intestinal stem cells protect their genome by selective segregation of template DNA strands. J. Cell Sci. 115: 2381–2388.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Prehn, R. T., 1977 Rate-limiting step in the progression of mouse breast tumors. Int. J. Cancer 19: 670–672.
    OpenUrlPubMed
  27. ↵
    Prehn, R. T., 1997 On the promotional role of symmetrical mitoses in carcinogenesis during regenerative growth in the rabbit ear. Cancer J. 10: 294–295.
    OpenUrl
  28. ↵
    Roth, R. B., and L. D. Samson, 2002 3-Methyladenine DNA glycosylase-deficient Aag null mice display unexpected bone marrow alkylation resistance. Cancer Res. 62: 656–660.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    Shaver-Walker, P. M., C. Urlando, K. S. Tao, X. B. Zhang and J. A. Heddle, 1995 Enhanced somatic mutation rates induced in stem cells of mice by low chronic exposure to ethylnitrosourea. Proc. Natl. Acad. Sci. USA 92: 11470–11474.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    Shinin, V., B. Gayraud-Morel, D. Gomés and S. Tajbakhsh, 2006 Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat. Cell Biol. 8: 677–687.
    OpenUrlCrossRefPubMedWeb of Science
  31. ↵
    Smith, G. H., 2005 Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template strands. Development 132: 681–687.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    Watt, F. M., and B. L. M. Hogan, 2000 Out of Eden: stem cells and their niches. Science 287: 1427–1430.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    Winton, D. J., M. A. Blount and B. A. J. Ponder, 1988 A clonal marker induced by mutation in mouse intestinal epithelium. Nature 333: 463–466.
    OpenUrlCrossRefPubMedWeb of Science
  34. ↵
    Zhang, W., E. Remenyik, D. Zelterman, D. E. Brash and N. M. Wikonkal, 2001 Escaping the stem cell compartment: sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations. Proc. Natl. Acad. Sci. USA 98: 13948–13953.
    OpenUrlAbstract/FREE Full Text
Previous ArticleNext Article
Back to top

PUBLICATION INFORMATION

Volume 174 Issue 3, November 2006

Genetics: 174 (3)

Issue highlights

  • Cancer and the Immortal Strand Hypothesis
  • Can Random Mutation Mimic Design?: A Guided Inquiry Laboratory for Undergraduate Students
  • Doubly Uniparental Inheritance Is Associated With High Polymorphism for Rearranged and Recombinant Control Region Haplotypes in Baltic Mytilus trossulus
  • Trans-Kingdom Transposition of the Maize Dissociation Element
  • Linear Element-Independent Meiotic Recombination in Schizosaccharomyces pombe
  • A Deletion at the Mouse Xist Gene Exposes Trans-effects That Alter the Heterochromatin of the Inactive X Chromosome and the Replication Time and DNA Stability of Both X Chromosomes
  • Chromatin-Modifiying Enzymes Are Essential When the Saccharomyces cerevisiae Morphogenesis Checkpoint Is Constitutively Activated
  • Misregulation of Sex-Lethal and Disruption of Male-Specific Lethal Complex Localization in Drosophila Species Hybrids
  • A Histone Methylation-Dependent DNA Methylation Pathway Is Uniquely Impaired by Deficiency in Arabidopsis S-Adenosylhomocysteine Hydrolase
  • Glyceraldehyde-3-Phosphate Dehydrogenase Mediates Anoxia Response and Survival in Caenorhabditis elegans
  • The Large Isoform of Drosophila melanogaster Heterochromatin Protein 2 Plays a Critical Role in Gene Silencing and Chromosome Structure
  • The Caenorhabditis elegans rhy-1 Gene Inhibits HIF-1 Hypoxia-Inducible Factor Activity in a Negative Feedback Loop That Does Not Include vhl-1
  • The WTM Genes in Budding Yeast Amplify Expression of the Stress-Inducible Gene RNR3
  • Large-Scale Gene Expression Differences Across Brain Regions and Inbred Strains Correlate With a Behavioral Phenotype
  • Drosophila Model of Human Inherited Triosephosphate Isomerase Deficiency Glycolytic Enzymopathy
  • Molecular Assembly of Meiotic Proteins Asy1 and Zyp1 and Pairing Promiscuity in Rye (Secale cereale L.) and Its Synaptic Mutant sy10
  • Genetic Evidence for Phospholipid-Mediated Regulation of the Rab GDP-Dissociation Inhibitor in Fission Yeast
  • Drosophila mus301/spindle-C Encodes a Helicase With an Essential Role in Double-Strand DNA Break Repair and Meiotic Progression
  • The Drosophila Fragile X Protein dFMR1 Is Required During Early Embryogenesis for Pole Cell Formation and Rapid Nuclear Division Cycles
  • dSno Facilitates Baboon Signaling in the Drosophila Brain by Switching the Affinity of Medea Away From Mad and Toward dSmad2
  • sli-3 Negatively Regulates the LET-23/Epidermal Growth Factor Receptor-Mediated Vulval Induction Pathway in Caenorhabditis elegans
  • Identification of a Novel Gene Family Involved in Osmotic Stress Response in Caenorhabditis elegans
  • Functional Characterization of Drosophila Translin and Trax
  • Dynamic Genetic Interactions Determine Odor-Guided Behavior in Drosophila melanogaster
  • Organization of the sex-ratio Meiotic Drive Region in Drosophila simulans
  • Mapping Quantitative Trait Loci Using the Experimental Designs of Recombinant Inbred Populations
  • Cumulative Effects of Spontaneous Mutations for Fitness in Caenorhabditis: Role of Genotype, Environment and Stress
  • Perfect Simulation From Nonneutral Population Genetic Models: Variable Population Size and Population Subdivision
  • Combining Bioinformatics and Phylogenetics to Identify Large Sets of Single-Copy Orthologous Genes (COSII) for Comparative, Evolutionary and Systematic Studies: A Test Case in the Euasterid Plant Clade
  • Testing for Effects of Recombination Rate on Nucleotide Diversity in Natural Populations of Arabidopsis lyrata
  • Statistical Tests for Detecting Positive Selection by Utilizing High-Frequency Variants
  • Evolution of the Human Immunodeficiency Virus Envelope Gene Is Dominated by Purifying Selection
  • Molecular-Genetic Biodiversity in a Natural Population of the Yeast Saccharomyces cerevisiae From “Evolution Canyon”: Microsatellite Polymorphism, Ploidy and Controversial Sexual Status
  • Pronounced Differences of Recombination Activity at the Sex Determination Locus of the Honeybee, a Locus Under Strong Balancing Selection
  • Phylogenetic Analysis of Fungal Centromere H3 Proteins
  • Types and Rates of Sequence Evolution at the High-Molecular-Weight Glutenin Locus in Hexaploid Wheat and Its Ancestral Genomes
  • Test of Association Between Haplotypes and Phenotypes in Case–Control Studies: Examination of Validity of the Application of an Algorithm for Samples From Cohort or Clinical Trials to Case–Control Samples Using Simulated and Real Data
  • Estimating Recombination Rates From Single-Nucleotide Polymorphisms Using Summary Statistics
  • Nonlinear Tests for Genomewide Association Studies
  • Genetic Variation in Drosophila melanogaster Resistance to Infection: A Comparison Across Bacteria
  • A Polymorphism in the 5′-Untranslated Region of the Porcine Cholecystokinin Type A Receptor Gene Affects Feed Intake and Growth
  • High-Resolution Quantitative Trait Locus Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals <800 kb in the Species-Conserved Niddm1i of the GK Rat
  • Amh and Dmrta2 Genes Map to Tilapia (Oreochromis spp.) Linkage Group 23 Within Quantitative Trait Locus Regions for Sex Determination
  • Mapping PrBn and Other Quantitative Trait Loci Responsible for the Control of Homeologous Chromosome Pairing in Oilseed Rape (Brassica napus L.) Haploids
  • Association Mapping of Complex Trait Loci With Context-Dependent Effects and Unknown Context Variable
  • A Thurstonian Model for Quantitative Genetic Analysis of Ranks: A Bayesian Approach
  • Dynamical Analysis of the Regulatory Network Defining the Dorsal–Ventral Boundary of the Drosophila Wing Imaginal Disc
  • A Gain-of-Function Screen Identifying Genes Required for Vein Formation in the Drosophila melanogaster Wing
  • Assignment of Rainbow Trout Linkage Groups to Specific Chromosomes
  • Genetic Dissection of Intermated Recombinant Inbred Lines Using a New Genetic Map of Maize
  • The Aspergillus nidulans rcoA Gene Is Required for veA-Dependent Sexual Development
  • Site-Specific Amino Acid Frequency, Fitness and the Mutational Landscape Model of Adaptation in Human Immunodeficiency Virus Type 1
  • A Clarification of the Hardy–Weinberg Law

SUBJECTS

  • Crow-Dove Perspectives

ARTICLE CLASSIFICATION

Perspectives
View this article with LENS
Email

Thank you for sharing this Genetics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Cancer and the Immortal Strand Hypothesis
(Your Name) has forwarded a page to you from Genetics
(Your Name) thought you would be interested in this article in Genetics.
Print
Alerts
Enter your email below to set up alert notifications for new article, or to manage your existing alerts.
SIGN UP OR SIGN IN WITH YOUR EMAIL
View PDF
Share

Cancer and the Immortal Strand Hypothesis

John Cairns
Genetics November 1, 2006 vol. 174 no. 3 1069-1072; https://doi.org/10.1534/genetics.104.66886
John Cairns
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation

Cancer and the Immortal Strand Hypothesis

John Cairns
Genetics November 1, 2006 vol. 174 no. 3 1069-1072; https://doi.org/10.1534/genetics.104.66886
John Cairns
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Related Articles

Cited By

More in this TOC Section

  • Illuminating Women’s Hidden Contribution to Historical Theoretical Population Genetics
  • Selective Sweeps
  • Mogens Westergaard’s Contributions to Understanding Sex Chromosomes
Show more Perspectives
  • Top
  • Article
    • PROTECTION BY THE CONTROL OF LINEAGE
    • PROTECTION BY THE SEGREGATION OF MUTATIONS
    • THE FINAL, POSSIBLY EPIGENETIC, STEP IN CARCINOGENESIS
    • Acknowledgments
    • References
  • Info & Metrics

GSA

The Genetics Society of America (GSA), founded in 1931, is the professional membership organization for scientific researchers and educators in the field of genetics. Our members work to advance knowledge in the basic mechanisms of inheritance, from the molecular to the population level.

Online ISSN: 1943-2631

  • For Authors
  • For Reviewers
  • For Subscribers
  • Submit a Manuscript
  • Editorial Board
  • Press Releases

SPPA Logo

GET CONNECTED

RSS  Subscribe with RSS.

email  Subscribe via email. Sign up to receive alert notifications of new articles.

  • Facebook
  • Twitter
  • YouTube
  • LinkedIn
  • Google Plus

Copyright © 2019 by the Genetics Society of America

  • About GENETICS
  • Terms of use
  • Advertising
  • Permissions
  • Contact us
  • International access