Medical Hypotheses 74 (2010) 377–382
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Medical Hypotheses
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Epigenetics: Origins and implications for cancer epidemiology
Melissa S. Nise, Puran Falaturi, Thomas C. Erren *
Institute and Policlinic for Occupational and Social Medicine, University of Cologne, Kerpener Strasse 62, 50937 Cologne-Lindenthal, Germany article info summary
Article history: This paper provides information on the evolution of the ‘epigenetics’ concept since Aristotle and draws Received 24 August 2009 attention to the importance of epigenetic implications for cancer epidemiology in the years to come. Accepted 6 September 2009 Clearly, to understand origins of the concept of epigenetics, it is worthwhile to consider historical argu- ments associated with evolution. Equally clearly, in the last half of the 20th century, great advances in the understanding of epigenetics and, more specifically, great advances in the understanding of epigenetics in cancer have been made. However, reaping the full benefits of epigenetics lies beyond the predominant experimental studies of today. In general, epigenetics opens many doors in the field of cancer, but it also adds another level of complex, inter-related, and multi-dimensional information to research, and to its interpretation. Overall, future cancer studies should consider, or at least be sensitive to, epigenetic effects and mechanisms. Moving the focus beyond ‘pristine’ inheritance via DNA alone, cancer epidemiology investigating epigenetic exposures such as environmental factors (exposure to heavy metals, air pollu- tion, arsenic and other toxins), dietary patterns (starvation, famine, contamination), and lifestyle habits (smoking, level of physical activity, and BMI) in populations has the prospect to significantly benefit future cancer prevention and treatment schemes. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction associated with evolution. The theory of evolution has in and of itself ‘evolved’. The mechanisms through which life develops Studies and observations concerning the biological develop- have occupied the minds of many well-known and respected ment of living organisms are long-standing and still ongoing. Aris- philosophers, theologians, and natural scientists, alike. Although totle pulled together existing theories and sparked new the more abstract questions pertaining to the meaning of life conversations regarding early development in his book De generati- have been juggled around without much, or any, progress, inqui- one animalium (On the Generation of Animals), where he alludes to ries about the developmental process have drastically changed the role of epigenetics in human development without citing spe- and advanced throughout the course of the last several hundred cific causes or explanations [1–3]. Thousands of years later, years. thousands of questions remain, particularly relating to the devel- Intriguingly, centuries before Darwin, the topic of evolution opment of abnormal cells, such as those found in cancer. was heating among scholars. Discussions favoring so-called Although many complicated scientific subjects are now well- preformation were eventually matched with those supporting understood and some are considered elementary (and almost triv- epigenesis. Preformation argues that a being (human or other- ial), numerous scientific answers, in particular, those related to the wise) is completely developed within the egg/germ and grows development of cancer, are still undiscovered. Understanding (and to adult form through nutrition. Whereas, epigenesis contends integrating) the roles of genes, genetics, and epigenetics seems to that the growth from egg/germ to adulthood is a develop- be a promising approach. As the intellectual capacity of genetics mental process, in which many factors play a role throughout and epigenetics in cancer continues to grow, so will the knowledge the lifetime of the organism. Epigenesis has proven to be a base for future studies (be they of epidemiological or experimental more accurate description of development, with a stronger nature), databases/catalogs, prevention measures, and treatments. evidence base, compared to the arguments favoring preforma- tion alone. A history of epigenetics A literary dissection of the word ‘‘epigenesis” into its two main components (‘epi’ and ‘genesis’) reveals the basic concept epigene- In order to better understand and appreciate the concept of sis employs. The prefix ‘‘epi-” stands for propositions such as, ‘epigenetics’, one must also consider the historical arguments ‘‘upon, besides, attached to, over, outer, after” [4]. ‘‘Genesis” is the ‘‘origin or coming to being of something” [5]. If one considers substituting ‘attached to’ for ‘epi-‘, a simplified definition of epi- * Corresponding author. Tel.: +49 221 4784450; fax: +49 221 4785119. E-mail address: [email protected] (T.C. Erren). genesis emerges, such that ‘epigenesis’ is something which is
0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.09.008 378 M.S. Nise et al. / Medical Hypotheses 74 (2010) 377–382 attached to / ‘‘in conjunction with” an organism’s materialization. 2. Wolff emphasizes the need for good science to have a balance Considering the actual definition of epigenesis, ‘‘the development between observation, theory, and experimentation. of a plant or animal from an egg or spore through a series of pro- 3. Wolff infuses the field of embryology with the doctrine of epi- cesses in which unorganized cell masses differentiate into organs genesis, strongly advocating that organisms develop over the and organ systems” [6], the two-part construction of ‘epi-’ and duration of their lifetimes [3]. ‘genesis’ offers a minimalist version, in this case ‘‘something”isa ‘‘series of processes”. Wolff’s experimentation influenced the embryologists Wilhelm As mentioned above, references to some of the chief principles of Roux, and compelled epigenesist Oscar Hertwig to argue that the epigenesis are described by academics as early as Aristotle; however, era in which Wolff made his exclamations had worked against the terminology and wording used today was not established until him. Hertwig writes, much later. According to Preus, ‘‘[Aristotle] knew that something ‘‘It was very different in earlier days; the acutest biologists and had to carry the dynamic structure from parent to child. His version philosophers were evolutionist, and an epigenetic* conception of the theory was a considerable advance on the theories of his pre- of the process of development could find no foothold alongside decessors...Not until the 19th century did epigenesis, the theory the apparent logical consistency of the theory of preformation. suggested by Aristotle, win general scientific approval,” [2]. Wolff’s Theoria Generationis (1759) failed to convince his con- The long delay in new information and the advancement of the temporaries, because he could bring against the closed system theory of epigenesis was largely due to the religious beliefs and of the evolutionists only isolated observations, and these doubt- available technology at that time, Roe explains; ‘‘it was much more ful of interpretation; and because, in his time, on account of the difficult to explain the development of the embryo epigenetically, rudimentary state of the methods of research in biology, men that is, through gradual formation of parts from unorganized mat- attached more importance to abstract reasoning than to obser- ter,” [7]. She continues to point out specific questions that hindered vation,” [11]. the advancement of embryological theory, even in a post-enlight- enment era, such as, ‘‘If the embryo develops through successive Therefore, the greatness of Wolff’s work was not able to be formation of structures, then where is the source of its eventual appreciated in the time period in which it was composed; hence, organization? What guides this process?” [7]. These questions, in the dormant century in the development of epigenetic theory. some respects, are still relevant today. Epigenesists are currently It appears that Hertwig’s publication which was translated into trying to pin-point the different driving forces that guide develop- English is one of the oldest articles to have used the word ‘‘epige- ment through epigenetics within specific areas of medicine. netic” (*). In his untranslated work, Präformation oder Epigenese? Despite the challenge of gaining followers within the scientific [12], Hertwig used the German word ‘‘epigenetische” as an adjec- community of the 16th century through innovative concepts, Caspar tive to describe the noun ‘‘Auffassung” (concept) (together meaning Friedrich Wolff attempted to answer these questions in their most ‘‘epigenetic concept”). However, the use of the word ‘‘epigenetic” fundamental sense. In an effort to surface the deep-seated flaws of in Hertwig’s case is not a one-to-one correlation with the ‘‘epige- preformationism, according to Roe, Wolff argued, ‘‘One can always netic” Conrad Waddington used when he wrote of the ‘‘epigenetic see the tiny particles, or globules, that are the basic components of landscape”. In Hertwig’s time, the concept of genetics was not all parts of the organism. But if the structure itself were preexistent, widely considered and the term ‘‘genetics” was not even coined only needing to become large enough to be visible, one should not be until 1905 [13]. Therefore, the first use of the word ‘‘epigenetic”, able to decipher its constituent parts before one sees the complete in the English language, was intended to describe processes which structure. ‘Therefore’, Wolff concludes in his dissertation [8], ‘that are strictly related to the theory of epigenesis, not genetics as parts are hidden because of their infinite smallness thereafter grad- Waddington later maps out. ually emerging is a fable,’” [7]. Waddington combined the two words ‘‘epigenesis” and ‘‘genet- It is unclear who the first scholar to use the term ‘‘epigenesis” ics” to form his theory of epigenetics. He purposed a new field of to describe the developmental theory was. The English physician, study (epigenetics) which should focus on finding the mechanisms William Harvey, noted in his Anatomical Exercises on the Genera- which cause already-known developmental processes to occur. tion of Animals (written originally in Latin [9] and translated into Waddington used basic principles from both fields of study to de- English by Dr. Robert Willis in 1847 [10]), ‘‘Now it appears clear fine the term epigenetics as he states, ‘‘...the task is to discover the from my history, that the generation of the chick from the egg is causal mechanisms at work, and to relate them as far as possible to the result of epigenesis, rather than of metamorphosis, and that what experimental embryology has already revealed of the all its parts are not fashioned simultaneously, but emerge in mechanics of development. We might use the name ‘epigenetics’ their due succession and order...” [10]. When one digs into the for such studies, thus emphasizing their relation to the concepts, original work of Harvey, Exercitationes de generatione animalium, so strongly favorable to the classical theory of epigenesis...” [14]. one finds that he uses the Latin term ‘‘epigenesin,” [9]. Wolff’s Roloff and Nuber interpret the term epigenetics spoken of by Wadd- dissertation, which was also written in Latin, contains the word ington in 1942 as a way ‘‘to describe the process by which geno- ‘‘epigenesin”, as well as the terms ‘‘epigeneseos”, and ‘‘epigene- type gives rise to phenotype, i.e. through causal interactions sis” [8]. Wolff used these words to identify the processes he wit- among genes (gene networks) and their products,” [15]. Therefore, nessed during his experiments with chicken embryos, as is in the the correlation, or causation, between genetic factors and the case of Harvey. Despite scholars during the 1600s utilizing resulting, developed organism was not clear among embryologists expressions referring to epigenesis, such as Harvey had done, in Waddington’s generation. However, Waddington did pin-point a claims have been made that those who drafted hypotheses prior very important aspect which had been widely overlooked by scien- to the 18th century were not able to make as large of an impact tists in the field of embryology prior to him. In his book, Introduc- on the theory of epigenesis or in embryology as Wolff had done. tion to Modern Genetics, he writes, According to Aulie, the work of Wolff particularly stands out ‘‘It is, surely, obvious that the fertilized egg contains constitu- among all of the embryologists of his time and before because ents which have definite properties which allow only a certain of three principles: limited number of reactions to occur; in so far as this is true, one may say that development proceeds on a basis of the ‘pre- 1. Wolff aimed to strike down the theory of preformation, once formed’ qualities of the fertilized egg. But equally it is clear that and for all. M.S. Nise et al. / Medical Hypotheses 74 (2010) 377–382 379
the interaction of the constituents gives rise to new types of tis- According to Esteller, a predominate researcher in the field of sue and organ which were not present originally, and in so far cancer epigenetics, Holliday is responsible for one of the most used development must be considered as ‘epigenetic’,” [16]. definitions of today, ‘‘heritable changes in gene expression that are not due to any alteration in the DNA sequence,” [20]. Waddington seems to successfully argue that both preforma- Nonetheless, a vast number of definitions have been used in the tion and epigenesis are important in the development of organ- last several decades. Due to this fact, early in 2009 Berger et al. sug- isms. He points out that genes exist from the very beginning of gested epigenetics be defined as, ‘‘an epigenetic trait is a stably the organism’s existence (compatible with ‘‘genetically coded” pre- heritable phenotype resulting from changes in a chromosome formation) and that development of the organism occurs in stages without alterations in the DNA sequence,” in order to create conti- thereafter (epigenesis). nuity among those in the scientific community [21]. Genes, therefore, are part of the missing link in Wolff’s theory of From an evolutionary perspective, in our view, epigenetic traits epigenesis, since he argued that nothing exists from the beginning may be conceptualized as fast, i.e. trans-generational, switches of which cannot be seen by the most powerful microscopes – what- gene expression. Intriguingly, these ‘‘fast switches” can enable ever appears, appears anew [3]. But, as insights into the key role organisms to react to environmental challenges, such as starvation of genes became available only in the 20th century – that genetic in a given generation, via epigenetic programming without altering information could be coded via DNA molecules was anticipated DNA sequences. in the early 1900s and the search for the precise structure was di- rected by physicist Schrödinger who provided an intelligibly-rea- soned prediction for what biologists should look for when Evolution of cancer epigenetics searching genetic material [17] – Wolff was, by necessity, unaware of genes and their great influence on organisms. Just as the term ‘epigenesis’ has evolved, so too has the term Waddington supplemented embryological development by ‘epigenetics.’ However, the knowledge and discoveries made with- combining scientific arguments and viewpoints which have been in the field of epigenetics are accumulating at a much faster rate in debate for centuries within the scientific community (Fig. 1). than those of epigenesis, due to the age in which epigenetics was Since the term ‘‘epigenetics” has been introduced, it has so also conceived. Just forty years after its main principles were communi- evolved and has grown away from Waddington’s simple causal cated by Waddington, the foundations for the epigenetics of hu- relationship between genotype and phenotype. Between the birth man cancer began to take shape. In his 1979 article, ‘‘A New of epigenetics as a part of developmental biology and today, many Theory of Carcinogenesis” [22], Holliday, according to Jablonka new discoveries have been made and opinions have changed on and Lamb, ‘‘suggested that heritable epigenetic changes in gene what epigenetics really entails. Robin Holliday is quoted as defin- expression are responsible for cancer,” [23]. Throughout the ing epigenetics as, ‘‘the study of the mechanisms of temporal and 1980s and early 1990s, breakthroughs in the relationship between spatial control of gene activity during the development of complex epigenetics and cancer poured out of many laboratories and re- organisms,” [15,18]. Several other definitions have surfaced search institutes. Feinberg and Vogelstein particularly solidified throughout the last 50 years due to the many different disciplines the junction between epigenetic modifications and human cancer involved and interested in the study of epigenetics. As Müller and in the early 1980s. More recently, revolutionary epigenetic treat- Olsson point out, ‘‘In using the term ‘epigenetic,’ developmental ments in some cancers have been/are being developed since it is biologists wish to emphasize the context-dependence of develop- now known that epigenetic mechanisms, such as DNA methyla- mental processes, geneticists refer to mechanism of gene regula- tion, are reversible [24,25]. It is without a doubt that the scientific tion that do not require changes of DNA sequence, evolutionary and medical communities have uncovered invaluable information biologists imply non-DNA-based mechanisms of inheritance, and about the epigenetics of cancer in the last 30 years. population geneticists evoke phenotypic variation in response to There are several mechanisms/modes in which epigenetics can environmental conditions,” [19]. Settling well among the four spe- be linked to cancer prevention, occurrence, development, and cialty fields listed by Müller and Olsson in 2003, today’s widely ac- treatment, such as DNA methylation (hypo-, hypermethylation), cepted definition of epigenetics consists of two parts: loss of genetic imprinting (LOI), and histone modification. How- ever, according to Ropero and Esteller, DNA methylation and his- (1) Changes in gene expression passed down by previous tone modification are the most predominant of the three with generations. respect to the epigenetics of mammalian cancer [26]. Nearly (2) Without changing the underlying DNA sequences. 30 years ago, researchers at Johns Hopkins, Baltimore, Maryland, USA ‘‘wondered what mechanism accounted for high-frequency ‘mutation’, adaptation to tumor microenvironment and plasticity in some cancers....At the time, many groups were excited by observations that DNA methylation might be linked to tissue-spe- cific gene silencing,” [27]. In 1983, Feinberg and Vogelstein showed the ‘‘loss of DNA methylation” (hypomethylation) in cytosine- phosphat-guanine (CpG) sites was more common in cancer cells compared to normal cells [28]. Further investigations revealed that hypomethylation contributed to every tumor type (benign and malignant) studied and moreover, ‘‘5-methylcytosine content was globally reduced,” [28]. These groundbreaking findings in epi- genetic cancer research lead the way into the next 25 years of can- Fig. 1. Components of C.H. Waddington’s definition of ‘‘epigenetics”. (a) The theory cer investigations and studies. of epigenesis signifies development within the organism after it has come into Although hypomethylation of DNA was the first known epige- existence. (b) Genes exist within the organism at the very being of existence (they netic mechanism associated with cancer development, historically, are ‘‘pre-formed”). (c) The development of an organism is ‘‘beyond”, ‘‘after”, ‘‘upon”, it was not the most commonly researched aspect of cancer epige- or ‘‘above” the existence of the organism, therefore, ‘‘Epi-” also serves to represent these words. (d) Genetics – the study of genes, or the heredity and variation of netics. This is not due to lack of interest, but rather to poor study organisms. design of research efforts. According to Feinberg and Vogelstein, 380 M.S. Nise et al. / Medical Hypotheses 74 (2010) 377–382
‘‘[Hypomethylation] was overlooked in preference of hypermethy- findings which are summarized by Feinberg and Tycko by stating lation for many years and is only now undergoing a renaissance. that ‘‘methylation of lysine 9 in histone H3 correlates with This is, in part, because of previous bias in experimental design; silencing of the CDKN2A tumor suppressor in cancer cells,” [27]. if one looks for altered methylation only at sites that are normally In addition to histone methylation, histone acetylation is another unmethylated, then one will only observe hypermethylation,” [28]. well-studied area within histone modification and cancer epigenet- Nonetheless, advances are currently being made in hypomethyla- ics. According to Fraga and Esteller, there are two main conse- tion with respect to cancer research in areas such as tumor classi- quences of histone acetylation. One is that the bond between the fication, diagnosis, and patient outcome predictions. histone and DNA is altered, and secondly, there are alterations in Just as Feinberg and Vogelstein had eluded in the early develop- the binding codes of chromatin-interacting transcription factors. ment of cancer epigenetics, it is now known that ‘‘the pattern of Furthermore, the level of histone acetylation depends on the balance DNA methylation changes substantially when cells become cancer- between two histone enzymes (histone acetyltransferases (HATs) ous...the tumoral genome becomes globally hypomethylated, un- and histone deacetylases (HDACs)) [33]. As shown by Nguyen like in normal cells, due mainly to the generalized demethylation et al., these alterations in histone modification affect genes which of the CpGs scattered throughout the body of the genes,” [26]. This are active in the development of sporadic cancers [34]. Tollefsbol global hypomethylation creates instability among the chromo- states, somal structure and thereby increases the probability of genomic rearrangements and facilitates oncogene activation, which leads ‘‘The alteration of the expression activity or targeting of histone to the development of cancer. Therefore, detection of global modifying enzymes such as the HDACs is central to both the ini- hypomethylation is an early sign of cancer and oncological devel- tiation and progression of cancer. It is through knowledge of the opment [29]. role of histone modifying proteins that has led to many of the A few years after Feinberg and Vogelstein published their find- extant histone-modifying anticancer drugs that have been ings regarding the hypomethylation of cancerous cells, Greger et al. developed. Other interventions in reducing cancer risk or pro- were the first to show that DNA methylation can effect tumor gression involve the impact of dietary influences on histone development through gene silencing. In 1989, Greger et al. pub- modifications in cancer,” [29]. lished their findings on the hypermethylation of CpGs islands in Despite alterations in histone modification (specifically, deacet- the retinoblastoma suppressor gene (RB gene) on chromosome ylation), future cancer therapies could include inhibitors of certain 13 in blood and tumor cells. Based on data they collected from deacetylase families (such as SIRT1) as well as dietary supplements 21 patients, they suggest, ‘‘that changes in the methylation pattern [29]. of the RB gene play a role in the development and spontaneous In addition to DNA methylation, LOI, and histone modification, regression of some retinoblastoma tumors,” [30]. Due to its effects there are other less predominate physiological changes which con- on tumor-suppressor gene silencing, hypermethylation is perhaps tribute to cancer epigenetics, such as non-coding RNA, chromo- the most studied aspect in cancer epigenetics today. According to some position effects, chromatin remodeling, polycomb group Tollefsbol, ‘‘Silencing of genes through hypermethylation can con- (PcG) proteins, and the processes of aging [29]. tribute to many of the hallmarks of cancer [31] including evading apoptosis, insensitivity to antigrowth signals, sustained angiogen- Epigenetics in cancer epidemiology esis, limitless replicative potential, and tissue evasion and metasta- sis,” [29]. Therefore, the reversal of over methylation in the Considering the role epigenetics plays throughout an individ- respective CpG sites in mammalian DNA is a very promising field ual’s lifetime and the means through which epigenetics effects of cancer therapy. individual cells (environmental factors, lifestyle influences, etc.) After the initial developments of DNA hypo-, and hypermethy- one of the next logical steps in the progression of epigenetic theory lation in cancer epigenetics were underway, Steenman et al. iden- is epigenetic epidemiology (Fig. 2). Epidemiology focuses on tified the relationship between the loss of imprinting (LOI) in the determinants of health and illnesses on a population-wide scale. insulin-like growth factor-II (IGF2) in most Wilms’ tumors (WT) and the inactivation of H19 as a tumor-suppressor gene through an epigenetic mechanism [32]. Although LOI had been previously investigated, the findings of Steenman et al. were important be- cause they were the first to link LOI with cancer. Moreover, the finding indicated epigenetic mechanisms as the cause. Feinberg and Tycko state, ‘‘These observations were the first to indicate a gatekeeper role for epigenetic alterations in cancer, as they are the earliest observable genetic change,” [27]. LOI gives insight to very specific epigenetic alterations through selective gene demethylation. Following the discovery of the affects of LOI in IGF2 in WT cells, histone posttranscriptional modification (histone modifica- tion) was shown to be the third epigenetic mechanism to be associated with cancer. Histone modifications, and more specifi- cally, the histone code (modifications within certain regions of the chromatin), are relative to their surroundings (i.e. chromatin, cell type, tissue type, etc.). Therefore, ‘‘before determining the al- tered patterns of histone modification in cancer, it is essential to identify the normal patterns in the corresponding region,” [33]. DNA methylation through histone modification has been known Fig. 2. Principle components of cancer epigenetics in relation to one another. Environmental factors, such as Ar, Cd, Ni2+, and nutrition, and inheritance all play a since the late 1980s. Histone modification with respect to gene role in the epigenetics of cancer mainly through DNA methylation and histone silencing in cancer cells, however, was not verified until less modification and occasionally due to loss of imprinting. *Environmental factors: than ten years ago by Nguyen et al. They [34] released their [39–41]; nutrition: [42]. **Inheritance: [43]. M.S. Nise et al. / Medical Hypotheses 74 (2010) 377–382 381
Jablonka defines epigenetic epidemiology as ‘‘the part of epidemi- epigenetic effects on cancer risks could be one explanation as to ology that studies the effects of heritable epigenetic changes on the why very similar replication studies in cancer epidemiology may occurrence and distribution of diseases,” [35]. She continues to de- have yielded different results. Indeed, in addition to having dili- scribe the advantages of this definition of epigenetic epidemiology gently classified exposure variables of interest, such as smoking as holistic since it incorporates ‘‘both cell-to-cell transmission of and/or asbestos, errors arising from the misclassification of expo- epigenetic variants during the individual’s lifetime, and trans-gen- sures due to one or more epigenetic factors, which are conceivably erational (between generations) inheritance,” [35]. relevant for the chain(s) of cancer causation may have been, for Cancer is of a particular interest in epigenetic epidemiology whatever reason, similar in groups being compared (nondifferen- since there are epigenetic candidate co-determinants of malignant tial), or they may have varied (differential). Disconcertingly, such neoplasms which have the potential to affect a large amount of the scenarios of relevant exposure misclassification in past epidemiol- population at one particular place and/or time. Holliday was ogic studies hold even more sobering implications. As uncontrolled the first to identify the importance of cell-to-cell epigenetics in epigenetic factors may have influenced cancer risks in any the field of cancer epidemiology. Jablonka writes, ‘‘[Holliday] has direction, and with unpredictable magnitude, at least some epide- argued that the inheritance of epigenetic defects, such as defects miologic cancer studies conducted in the past may be uninterpret- in DNA methylation (which he called epimutations), can underlie able. Note that what is illustrated here with regard to cancer...” [35]. Moving beyond ‘‘pristine” inheritance via DNA epidemiologic studies is certainly valid for, at least some, experi- alone, population-wide exposures may cause or contribute to can- mental studies and could alter or disallow interpretations of some cer or other diseases through epigenetic means such as environ- experiments of the past as well. mental factors (exposure to heavy metals, air pollution, arsenic It follows for the design of future studies, be they of epidemio- and other toxins), dietary patterns (starvation, famine, contamina- logical or experimental nature, that they should consider, or at least tion), and lifestyle habits (smoking, level of physical activity, and be sensitive to, epigenetic effects and mechanisms. With regard to BMI). Considering the nexus between environmental factors and epidemiologic investigations, Wild rouses the call to action by stat- epigenetics when investigating cancer developments can be a rec- ing, ‘‘Molecular epidemiology must begin to address the question as ipe for success, which may be evinced by a landmark study by Lich- to how exposures, such as diet, obesity, physical exercise, environ- tenstein and colleagues, published in 2000 [36]. The highly-cited mental chemicals, etc., influence methylation, histone modification epidemiological investigation provided robust evidence from some or other epigenetic processes to alter cell function and cancer risk,” 44,000 pairs of twins which revealed that the scientific community [25]. Therefore, there is an entire spectrum of cancer epigenetic should attempt to identify cancer causes or contributors in the studies which needs to be filled: from broad, standardized data gen- environment because inherited genetic factors can merely explain eration and communication to specific epigenetic aspects of differ- the minority of most types of neoplasms [36]. ent cancers at different stages of development. Understanding the occurrence and distribution of cancers or Bernstein et al. comment, ‘‘The past few years have seen epigenetic pre-cursors to cancer can greatly affect treatment and remarkable progress in our ability to characterize epigenetic mod- future cases. Wild purposes to use molecular epidemiology to ifications at a global scale, and some enlightening patterns have map out the epigenetic biomarkers for certain cancers. He claims, begun to emerge,” [37]. Despite this praise for the epigenetic re- ‘‘One of the most exciting future challenges for molecular epidemi- search community, they continue by stating, ology is the development of an analogous set of biomarkers for ‘‘Computational tools are urgently needed to analyze and inte- exposures acting through other mechanisms of carcinogenesis. grate the diverse epigenomic data being generated. Existing This follows the recognition that environmental exposures can al- tools have largely been adapted from platforms designed for ter gene expression not only by mutation but also by epigenetic other problems and are suboptimal. It will be important to mechanisms,” [25]. Therefore, the actions which induce epigenetic develop new approaches that consider the unique attributes changes in cells which stimulate cancer generation and progres- of epigenomic data and can integrate high-resolution data on sion should be sought out through epidemiological observations cytosine methylation, histone modifications, chromatin as well as experimental in order to create a ‘‘database” of biomark- domains, and boundaries across different tissues and develop- ers and pre-cursors for future cancer patients. Jablonka and Lamb mental stages,” [37]. agree, stating, ‘‘epidemiological research programs and medical practice will have to accommodate information like this and devel- op ways of recognizing, avoiding, and curing disorders caused by Both continued study efforts and the development of tools are epigenetic changes,” [35]. part of the Human Epigenome Project (HEP), which would serve as a supplement to the recently completed Human Genome Pro- ject. Participants of an American Association for Cancer Research What does epigenetics mean for the interpretation of past (AACR)-sponsored workshop focusing on the HEP, drafted a mis- investigations and the design of future studies? sion statement to guide future epigenome endeavors worldwide. Jones and Martienssen report, ‘‘The goal of the Human Epigenome Although great advances in the understanding of epigenetics Project is to identify all the chemical changes and relationships have been made in the last half of the 20th century, and more spe- among chromatin constituents that provide function to the DNA cifically, great advances in the understanding of epigenetics in can- code, which will allow a fuller understanding of normal develop- cer within the last quarter of the century, reaping the full benefits ment, again, abnormal gene control in cancer, and other diseases of epigenetics lies beyond the data, experiments, studies, and tech- as well as the role of the environment in human health,” [38].In nology of today. Epigenetics opens many doors in the field of can- an attempt to successfully break ground on this enormous under- cer, but it also adds another level of complex, inter-related, and taking, the taskforce calls upon the expertise, technologies, and re- multi-dimensional information to future studies. sources of laboratories across the world, as well as for educators to With regard to the interpretation of past investigations, consid- inform politicians and decision makers about the need for such a ering epigenetic risk factors certainly adds complexity. To explain scientific/medical venture. this viewpoint, let us assume that epigenetic factors do have mod- Epigenetics ultimately demands a high-end organizational sys- erate, let alone substantial, influence on cancer risks in popula- tem. An extremely structured approach to future epigenetic data tions. With such premise, not having considered or controlled for generation and collection which is observed by all parties involved 382 M.S. 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Adelaide: of H19 in Wilms’ tumour. Nat Genet 1994;7:433–9. eBooks@Adelaide. The University of Adelaide Library; 2007. 学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源， 提供一站式文献检索和下载服务”的24 小时在线不限IP 图书馆。 图书馆致力于便利、促进学习与科研，提供最强文献下载服务。 图书馆导航： 图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具