© The Author 2008. Published by Oxford University Press.
Chromosomal Translocations in Childhood Leukemia: Natural History, Mechanisms, and Epidemiology
Affiliation of author: Department of Epidemiology and Biostatistics, University of California, San Francisco, CA
Correspondence to: Laboratory for Molecular Epidemiology, 1 Irving Street, AC-34, University of California, San Francisco, CA 94143-0441 (e-mail: joe.wiemels{at}ucsf.edu).
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ABSTRACT |
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 Top Abstract IntroductionTwo-Hit Disease: LeukemiaNatural History: Timing of...Secondary EventsLessons from Translocation...Lessons from EpidemiologyThe FutureReferences |
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The root causes of childhood leukemia will be discovered by understanding the mechanism of mutations in the context of the cell of origin and time in life of the child. Molecular studies using archival DNA samples and twins with concordant leukemia have demonstrated that most childhood leukemia translocation subtypes occur before to birth and occur in early progenitors. Translocation breakpoints typically harbor evidence of nonhomologous end-joining repair mechanisms, but in only a few examples are the causative mechanisms of breakage evident, such as V(D)J recombinase gene activation. Epidemiologic differences in the rates of translocations between populations may point to causal clues. Leukemia like all cancers is the product of two or more genetic and/or epigenetic events, and the natural history and mechanisms of these two events are likely independent, resulting in two or more "causes" of leukemia. Complementary mutations include point mutations, deletions, and epimutations, which have distinct associated causal mechanisms.
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INTRODUCTION |
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TopAbstractIntroductionTwo-Hit Disease: LeukemiaNatural History: Timing of...Secondary EventsLessons from Translocation...Lessons from EpidemiologyThe FutureReferences |
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Childhood leukemia is a clinical success story, with greater than an 80% cure rate, depending on the phenotype and tumor genetics. However, most cured children face long-term sequelae such as heart defects or chronic ailments (1), and prevention and early detection of this disease is a goal. Apart from rare cases with clear etiology (genetic predisposition or radiation), we are still a long way from understanding the causes in the majority of leukemia cases. Although biologists often speak of translocation and mutations as the "cause" of leukemia, the molecular formation of these alterations by endogenous processes (cellular enzymes, oxidation by-products, spontaneous events) and exogenous factors (infection, chemicals, and radiation) is the true root cause and is unknown for most leukemia patients. We describe the current state of affairs and new epidemiologic approaches that may make headway in this area.
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Two-Hit Disease: Leukemia |
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TopAbstractIntroductionTwo-Hit Disease: LeukemiaNatural History: Timing of...Secondary EventsLessons from Translocation...Lessons from EpidemiologyThe FutureReferences |
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Childhood leukemia, like all cancers, is a product of alterations to the germline genetic and epigenetic code in the appropriate cell population, resulting in a clonal disease. The hematopoietic organ harbors in its native state the capacity to disseminate cells throughout the body, whether stem, progenitor, or terminally differentiated, and therefore requires fewer alterations than solid tumors. A minimum of two events, one leading to enhanced proliferation (with disabled apoptotic fallbacks) and the other a block in differentiation, may be sufficient (2). Leukemia cells tend to be "simple" genetically with fairly stable genomes and often three or fewer observable changes (3). Of the known genetic events leading to pediatric leukemia, translocations leading to fusion transcription factors or activated signaling kinases are among the most common events, along with aneuploidy, deletions in cell cycle checkpoint genes, and mutated genes in FLT3, RAS, and other growth-promoting pathways (4).
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Natural History: Timing of the Translocation as First Hit |
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TopAbstractIntroductionTwo-Hit Disease: LeukemiaNatural History: Timing of...Secondary EventsLessons from Translocation...Lessons from EpidemiologyThe FutureReferences |
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The very short latency of leukemia, combined with the extreme developmental and cellular kinetic stress of a developing fetus, argues for a prenatal origin for most leukemia subtypes. Unique studies developed by Mel Greaves and colleagues concerning the natural history of leukemia have utilized twins with concordant leukemias, as well as archived newborn blood spots, to prove that genetic events leading to leukemia can occur before birth (5,6). Clear evidence exists for in utero origin of several leukemia translocations including TEL-AML1 (7–9), AML1-ETO (10), PML-RARA, and CBFB-MYH11 (11) (Figure 1). Interestingly, these are all translocations, and a point mutation has not yet been reported to occur prenatally. Although technical problems of "backtracking" point mutations may be part of the reason, this may indicate that translocations are either tolerated better during the prenatal period (immunologic naivety of the host) or are more easily formed during a period of high cell division in progenitor populations with oxidative or folate stress. At least one mutation type, insertion or deletion at the GATA1 locus, has also been found to occur prenatally in Down’s syndrome patients with transient myeloproliferative disorder and AML-M7 (12).
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Whether translocations are a product of errors in normal DNA processing or caused by external factors (chemicals, viruses) is not known, but current evidence suggests that translocations are perhaps 100-fold more common in the population than their associated leukemias (13,14). This indicates that most translocations are not sufficient for disease but may be predictive for future risk of leukemia in those children harboring the fusions.
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Secondary Events |
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TopAbstractIntroductionTwo-Hit Disease: LeukemiaNatural History: Timing of...Secondary EventsLessons from Translocation...Lessons from EpidemiologyThe FutureReferences |
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Understanding causes of leukemia does not end with the initiating event, but rather with an understanding of an examination of the subsequent event(s) that lead to a diagnosis of leukemia. Some leukemia subtypes have clear associations with secondary events—TEL-AML1 translocation with deletion of the contralateral 12p arm (15), and MLL and high hyperdiploidy with RAS pathway mutations including KRAS2, NRAS, FLT3, and BRAF (16–20). These secondary "hits" may be the rate-limiting events for leukemia, and our efforts to understand the causes of leukemia in current case–control epidemiology studies may inevitably be focused on the second hit because of this temporal sequence, lessening our ability to perceive the causes of the translocations.
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Lessons from Translocation Structure |
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TopAbstractIntroductionTwo-Hit Disease: LeukemiaNatural History: Timing of...Secondary EventsLessons from Translocation...Lessons from EpidemiologyThe FutureReferences |
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MLL
The most heavily studied translocation subtypes are the MLL translocations, which are common in two groups of patients—those who were previously treated for other cancers with topoisomerase II–inhibiting drugs and infants. This common epidemiology suggests that naturally occurring or medicinal substances with anti–topoisomerase II activity might be involved in infant leukemia. Infant MLL breakpoint distributions are sometimes reported to be similar to those from therapy-related patients (21,22) and different from adults (23). A strong breakage and scaffold attachment site is located in the MLL breakpoint cluster region (24,25), leading to the hypothesis that topoisomerase II cuts at this site causing the translocation; however, any agent that activates apoptotic endonuclease, CAD, has the same functional consequence but does not usually cause translocations in MLL (26). The presence of bona fide topoisomerase II–binding sites at the breakpoint fusion in therapy-related leukemias [in many locations apart from the CAD nuclease site, reviewed in (27)] suggests that stabilization of the "cleavable complex" between anti–topo II agents and the enzyme is the critical activity rather than the activation of apoptotic endonucleases. Such topo II–binding sites have not been located at infant MLL breakpoints, but such an analysis may be possible with the discovery of dietary, chemical, or medicinal substances associated with this leukemia subtype (28,29).
TEL-AML1, AML1-ETO, PML-RARA, and CBFA2-MYH11
These translocations are grouped together here for two reasons—first, they all demonstrate evidence of prenatal origin; second, they all display evidence of dispersed breakpoint distribution (ie, not clustered) and fusion by nonhomologous end-joining (NHEJ) processes, with high conservation of sequence (Figure 2, TEL gene). The lack of site-specific clustering of these fusions, in contrast to translocations with defined molecular origins (as found in lymphomas), suggest that these fusions form in progenitor cells before the expression of recombinase-activating genes (30). The translocations themselves may occur in uncommitted progenitors but prove to be functionally relevant in later stage progenitors of myeloid or lymphoid subtype. To date, no data link specific risk factors to any of these translocations among children, although the AML1-ETO translocation is putatively associated with benzene metabolites in adults (31), and with MLL is associated with prior topoisomerase II inhibitor therapy (32). Like MLL, the AML1 gene harbors a CAD-endonuclease site (33), which may be relevant to its association with topo II inhibitors (34).
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The E2A-PBX1 translocation is an outlier from the group above, regarding mechanism. This translocation appears to occur in the context of a normal pre–B cell that has activated its V(D)J recombinase machinery and already passed through a positive antigen selection, given that nearly all E2A-PBX1 patients have in-frame functional IGH rearrangements (35). The translocation is also highly clustered harboring nontemplate nucleotides reminiscent of a V(D)J joint occurring postnatally (35) (Figure 2, E2A gene). This circumstantial evidence points to a site-specific mechanism, most likely the RAG complex that can cleave DNA in the absence of heptamer–nonamer recombinase site sequences (RSS) at positions of DNA secondary structure (36,37). E2A-PBX1 thus shares some characteristics of the more mature B-cell tumors, the lymphomas.
Secondary rearrangements to the TEL-AML1 translocation are by now well characterized, the most common being a deletion in the short arm of 12p. These deletions display a unique causal pattern, being associated with retrotransposon sequences ( J. Wiemels, submitted), although like translocations the initiating cause of the breakage event is not yet described. For secondary rearrangements, risk factors pertaining to infection or immune response may be more relevant for causality given demonstrated associations between childhood infection and leukemia risk (38).
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Lessons from Epidemiology |
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TopAbstractIntroductionTwo-Hit Disease: LeukemiaNatural History: Timing of...Secondary EventsLessons from Translocation...Lessons from EpidemiologyThe FutureReferences |
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Lessons from other cancers suggest that the variations in incidence rates of specific subtypes of cancer between different populations are caused by different prevalence of environmental factors (39). Such differences are beginning to emerge for subtypes of leukemia. These differences first emerged on studies looking at variation in treatment response among different ethnicities in the United States, which is driven in part by a deficit of better risk categories including the "common" variant of childhood ALL among African Americans (40–42). The relative frequency of specific translocation subtypes of leukemia varies several-fold among populations with different rates of cancer as well as among different ethnic groups in the same population (3).
Apart from the incidence of translocations in leukemia cases is the incidence of translocations in the general population, being far more common (13,14,43). It is not clear whether translocations themselves (in the absence of a leukemia diagnosis) actually vary between populations. If this were the case, environmental or genetic differences between populations may be responsible for differential translocation rates among patients. Alternatively, translocations may occur at a constant background rate in all populations, but those risk factors that induce the postnatal "second hit" vary by specific population. The answer to this question is unresolved but has profound implications on leukemia prevention. Much of the epidemiology of leukemia currently focuses on postnatal factors in particular those pertaining to the immune system—early daycare, vaccinations, birth order, infections, etc; with some clear associations, indicating that postnatal factors play a large role. Whether we are currently "masked" to the identities of the environmental factors that induce translocations (as an early in utero event) by our current epidemiology study designs is not clear.
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The Future |
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TopAbstractIntroductionTwo-Hit Disease: LeukemiaNatural History: Timing of...Secondary EventsLessons from Translocation...Lessons from EpidemiologyThe FutureReferences |
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Because translocations largely appear to be the initiating event in leukemia and occur at much greater frequency than leukemia, the current paradigm of case–control epidemiology studies of leukemia are an inefficient means to explore their causes. Much more appropriate is the study of translocations in the population as a whole in prospective cohorts. Such studies provide the best epidemiologic information (obtained prospectively and without disease) and most useful biological samples for the study of the natural history and causal mechanism for translocations and other leukemia-generating mutations. The newly formed International Childhood Cancer Cohort Consortium will provide a framework to explore incidence of initiating events such as translocations among normal born enrolled in several new cohort studies worldwide and assess the pregnancy-associated risk factors for such events. These studies, such as the US National Children's Study and the Chinese Children and Family Cohort, will permit the assessment of factors that lead to leukemia progression in children born with translocations.
Epidemiology studies are capable of demonstrating association between risk factors and disease but need to be designed around the natural history of disease as well as clear biological mechanisms for maximal effectiveness. Population-based and laboratory studies must inform each other for our future progress in understanding the etiology of leukemia. The ultimate goal is prevention, likely possible via early detection combined with prophylactic measures.
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