© The Author 2008. Published by Oxford University Press.
Brief Historical Sketch of Chromosomal Translocations and Tumors
Affiliation of author: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Health and Human Services, Bethesda, MD 20892
Correspondence to: Michael Potter, MD, Laboratory of Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Health and Human Services, Bethesda, MD 20892 (e-mail: potter{at}helix.nih.gov).
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ABSTRACT |
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 Top Abstract Discovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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The discovery of chromosomes emerged from the cytological analysis of mitosis in the 1870s. At the turn of the 20th century, cytologists and geneticists established that chromosomes carried the hereditary material. In the early 20th century, Theodore Boveri, recognizing the nonequivalence of individual chromosomes, began thinking about the biological consequences of imbalances of chromosomal compositions in somatic cells and how these might explain the origin of cancer. Many of his predictions would have to wait for confirmation until the 1950–1960s, when mammalian cytogenetics became feasible with the use of ascites tumors as sources of metaphases. This advance coupled with the discovery of G banding by Caspersson and his associates led to finding characteristic recurring chromosomal abnormalities in certain kinds of tumors. Chromosomal translocations that were associated with promoter deregulations or the formation of novel fusion genes were the prime models. This continuing progress combined with dramatic advances in DNA structure, transcription, and repair have provided new insights into the role of this class of mutations in neoplastic development.
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Discovery of Chromosomes in the 1870s |
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TopAbstractDiscovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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With the availability of much improved microscopes and histological methods, biologists in the 1870s began focusing on the details of cell division. It was in this period that chromosomes (threads) and their curious behavior during cell division became the focus of the science of cytology (see historical review by Henry Harris) (1). Walther Flemming called the series of changes within the nucleus as "karyomitosis" (thread-like metamorphosis) and introduced the term mitosis, a historical landmark in biology (2,3). The period of 1870–1900 was a golden age for cytology (4) and "on its heels" came the rediscovery of Mendelian Genetics in the early 1900s. This focused attention again on the nature of the units of heredity. The realization that chromosomes were the carriers of these units in 1902–1903 is attributed to Walter S. Sutton (5) an American graduate student and the renowned German embryologist Theodore H. Boveri (6) who early on recognized the nonequivalence of chromosomes and intuitively believed they were the carriers of genetic information. An early concept of chromosome substructure emerged from the demonstration of linked genes and crossing over by the hands and perceptive eyes of the great Drosophila geneticists Thomas Hunt Morgan, Alfred Sturtevant, Calvin Bridges, and Herman J. Muller (7,8). The secret of the units of hereditary and how they were related to the chromosome was much debated (7,9).
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Chromosomal Translocations and Other Manifestations of Chromosomal Instability: 1920-1930s |
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TopAbstractDiscovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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Implicit in crossing over was the requirement for chromosome breakage and rejoining but how this happened was not understood. It was during a later study of linked genes in 1921 that A. H. Sturtevant noted another example of chromosome breakage when he found that pieces of chromosomes could not only recombine with their homologues but occasionally segments of a different chromosome. "A section, including the peach locus, broke loose and attached itself near the right-hand end of a normal third chromosome" (ie, translocation) (10). "Segmental interchanges" was another term for chromosomal translocations (CTs) used by Belling (11). CTs, insertions, and inversions became the subject of extensive studies in the late 1920s and 1930s.
Important advances in 1926–1927 were the discoveries of the mutagenic effects of X-rays in Drosophila by Herman J. Muller (12) and in Barley and Zea Mays by Lewis J. Stadler (13). This provided a wealth of new mutations in genetically well-studied species. As Muller stated "... ionizing radiations ... induced point mutations in abundance also induced structural changes of all known types" (9) including translocations, inversions, insertions, dicentrics, and deletions. Barbara McClintock who had described the 10 different chromosomes in Zea Mays and could distinguish each by chromomere patterns was invited by Stadler to come to Missouri and work on the mutants he had produced. She described the behavior of dicentric chromosomes in mitosis and the breakage-fusion-bridge cycle (14,15). These were the beginnings of chromosome ("genome" was the term she used) instability so provocatively described in her Nobel lecture: "In the future attention undoubtedly will be centered on the genome, and with greater appreciation of its significance as a highly sensitive organ of the cell, monitoring genomic activities and correcting common errors, sensing the unusual and unexpected events, and responding to them often by restructuring the genome" (16).
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Boveri’s Thoughts on Chromosomes in Cancer in 1914 |
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TopAbstractDiscovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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In the first half of the 20th century, there began serious speculations, hypotheses, and some data about the role of chromosomes in cancer. These thoughts were largely based on observations made in plant, invertebrate, and amphibian developing cells and not directly in neoplastic tissues, which were rarely found in these species. The study of chromosomes in mammals where neoplastic diseases were abundant was undeveloped. Nonetheless, challenging ideas and speculations were generated about cancer. The most insightful and indeed prophetic ideas were made by the outstanding developmental biologist Theodore Boveri based on experimental observations with developing Sea Urchin eggs in 1902–1903. Essentially, he fertilized haploid egg cells with two sperms that generated two mitotic spindles with only a triploid set of chromosomes. The chromosomes were distributed unequally to the four blastomeres. When a full complement of chromosomes occurred, the embryo developed normally from a blastomere, but when there were deficiencies, defects occurred. From this Boveri had proposed the idea as early as in 1903 that "different qualities belong to different chromosomes." He even proposed that some chromosomes carried "inheritance factors" that suppressed cell division and that: "cells of tumors with unlimited growth would arise if these inhibiting chromosomes were eliminated." He went on: "... the essence of my theory is not abnormal mitosis but a certain abnormal chromatin complex not matter how it arises ... This primordial cell of a tumor as I shall call it in what follows is according to my theory a cell which contains as a result of an abnormal process a definite and wrongly combined chromosome complex. This above all is the cause of the tendency to rapid proliferation which is passed on to all the descendents of the primordial cell" (17). These ideas reflect a conceptual understanding of a connection of the genetic apparatus embodied in chromosomes to the origins of neoplasia far ahead of his time.
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Cytogenetics in Mammalian Tumor Cells Begins in Ernest 1950–1976 with Metaphase Banding Patterns and the Identity of Individual Chromosomes |
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TopAbstractDiscovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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This was a period of exciting and revolutionary discoveries in cytology that began in the laboratory of Torbjorn Caspersson and opened the door for studying chromosomes in mammalian species where tumors were unfortunately much more prevalent. In 1947, two very talented Hungarian medical students George and Eva Klein came to Caspersson's laboratory at the Karolinska Institute in Stockholm looking for a new home in the world of science and genetics (18). Caspersson had developed spectrophotometric methods (UV spectrophotometry) to determine the location and quantity of nucleic acids in cellular organelles. After some disappointing early attempts to work with fixed mammalian tissue sections, the Kleins learned about the Ehrlich Ascites Tumor at a lecture given by Hans Lettré and recognized its potential for mammalian cytogenetics. The Kleins introduced this tumor into Caspersson's laboratory as a source of mammalian cells in suspension. One can only assume that Caspersson was impressed with this model and the Kleins as well as he urged them to develop this project. In 1950, an opportunity opened up for Caspersson to send two young students to the United States for a brief fellowship of several months. He selected George Klein (GK) as one of his choices and sent him to the laboratory of an old friend and collaborator Jack Schultz at the Institute for Cancer Research at Fox Chase, Philadelphia. Caspersson and Jack Schultz had worked together before WWII and formed a great friendship and correspondence. They even analyzed the bands in salivary gland polytenic chromosomes using Caspersson's instruments (19). When GK arrived at Fox Chase, he was introduced to Theodore S. Hauschka, and these two "enthusiasts" wasted no time in acquiring every available mouse tumor and converting each into ascites tumors (20). In turn, Hauschka introduced GK to tumors in inbred mice and the genetics of tissue transplantation. GK soon returned home loaded down with 200 mice that he personally escorted from Philadelphia to Stockholm. Hauschka began studying the chromosome numbers and ploidy in ascites tumors.
In 1952, the well-established plant cytogeneticist Albert Levan from Lund became interested in extending his studies to mammalian systems, and this led him to Hauschka's laboratory in 1952–1954 at Fox Chase to work on chromosomes in mouse ascites tumors. One of Levan's first experiments focused on comparing the length of chromosomes in mouse spermatagonia with those in ascites tumor cells, and a remarkable difference was discovered. Some of the chromosomes in the tumors were longer or shorter than the longest or shortest chromosomes in spermatagonial cells. He reasoned that these must have arisen by CTs (21). Interchromosomal translocations may also lead to recognizable "types of new chromosomes," He called these "cryptostructrual rearrangements" (21,22) and this was confirmed independently by Hauschka (23). Levan noted "... the structural remodeling of the chromosome set has played a more important role in the development of a tetraploid tumor idiogram than in diploid." Levan recalled that tetraploid plants were more adaptable than their diploid counterparts to environmental changes. The proof that some of these cryptostructural rearrangements were in fact translocations awaited the development of a method for identifying individual mammalian chromosomes in 1972 and 1973. These were some of the beginnings of chromosomal instability in mammalian tumor cells that sparked the remarkable discoveries that followed.
A major advance in chromosomal disorders in neoplasia in the 1950–1975 period was made by Peter Nowell and David Hungerford (24). They sought to study the chromosomes in human tumors but not having the advantages of transplantable ascites tumors began using human peripheral blood leukemic cells. Short-term cultures of these cells contained metaphases, but then they discovered that an available mitogen, phytohemagglutinin, induced an abundance of mitotic figures (25). This allowed them to survey a great variety of human leukemic cells and here they discovered a subtle but highly significant anomaly in the leukemic cells of patients with chronic myelogenous leukemia (CML), specifically a characteristic minute chromosome that became known as the Philadelphia chromosome (24). This turned out to be a consistent recurring phenomenon in CML, and a whole new field of investigation was born. Cytology had entered the practical world of the medical clinic.
To crown the remarkable achievements of this period from 1950 to 1975 was the discovery of banding patterns in metaphase chromosomes made possible by Torbjorn Caspersson, Lore Zech, and their colleagues (26). Now, in both humans and mice, it became possible to identify each of the unique chromosomes in well-spread metaphase plates. This revolutionized mammalian cytogenetics and brought it into the world of diagnostic medicine. The first to develop this was Janet Rowley in 1972 who identified the Philadelphia chromosome as a one partner in a reciprocal translocation. Then in 1973, she identified the first recurring CT in human acute leukemia t(8;21) and this was the beginning of an exciting series of studies in her laboratory and others that have led insights into the causes and pathogenesis of acute leukemias in humans.
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1975–2000: Consistent Recurring Breaksites |
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TopAbstractDiscovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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In 1965, George Klein had become interested in the pathogenesis of an unusual B cell lymphoma in African children that was associated with disfiguring jaw tumors (18). These dramatic tumors had been discovered by Denis Burkitt in Africa and bear his name as Burkitt Lymphomas (BL). Through an extensive series of discoveries, endemic BL became associated with the ubiquitous human Epstein Barr virus. GK was eager to obtain tissues for his laboratory in Stockholm to study this fascinating model system. After numerous enquiries, he located an ENT surgeon in Nairobi, Peter Clifford, who began sending him specimens on a weekly basis. GK's whole laboratory set about culturing and analyzing these tissues that arrived on ice every Tuesday. When Caspersson developed chromosome banding, cytological studies were initiated. Two Bulgarian workers Manolov and Manolova at the Karolinska with the help of Albert Levan found that BL tissues consistently and recurrently contained Chr 14q+. Their study was discontinued when they had to return home (27). Lore Zech continued the work and identified that the origin of the chromosomal fragment attached to 14q+ was from chr8, thus identifying the t(8;14) CT for the first time in BL (28). GK and his colleague Francis Wiener then began to search for experimental models and focused first on plasma cell tumors (PCTs) in mice. Reports by T. H. Yosida (29) and G. Sorenson et al. (30) had described recurring t(12;15) and t(6;15) CTs in long-term transplanted PCTs, but GK wished to analyze a consecutive series of primary or first-generation PCTs. This study showed that these CTs were consistent and recurrent in pristane-induced PCTs (31). GK and FW then contacted Hervé Bazin who had developed a spontaneous rat immunocytoma model system and again found recurring IgH/C-Myc, t(6;7) CTs in each of the tumors (32–34). The t(6;7) was the rat homologue of t(8;14) and humans and t(12;15) in mice.
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Oncogenes at Breaksites: The Promoter Insertion Hypothesis 1980–1983 |
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TopAbstractDiscovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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Detailed analysis revealed that the breaksites in these CTs from three different species occurred in the same bands in each of the tumors, and the "race was on," to identify the genes at these breaksites. Two seminal observations led to their identity. The first came from a study on the role of the Avian Leukosis Virus (ALV) in bursal lymphoma development in chickens. ALV did not possess transforming activity, but infection of chickens by ALV was responsible for epidemics of B cell lymphomas that decimated flocks of chickens. These occurred after long latent periods. Because ALV was not associated with a transduced oncogene, its role in lymphoma development was not clearly defined. Through reverse transcription the RNA genome of the ALV virus during an active infections was able to insert itself randomly into the chicken chromosomal genome. William Hayward, Benjamin Neel, Harriet Robinson, and Susan Astrin postulated that the insertion of the ALV following an infection might activate a critical oncogene by placing it under the control of ALV promoters located in the long terminal repeat (LTR) sequences (35–37). These workers postulated the ALV virus might insert itself next to a cellular oncogene and take over its regulation. They systematically tested the known oncogenes in the chicken to see if LTRs of ALV had inserted into one of these genes and discovered that C-Myc was consistently targeted and driven by ALV insertion in 28 different bursal lymphomas. This was a stunning advance because it established the concept of insertional mutagenesis.
The second turning point observation inspired by the bursal lymphoma story was made by Grace Shen-Ong and Michael Cole who looked for rearrangements of c-Myc caused by CTs. They found consistent myc rearrangements in mouse PCTs (38) and further identified the genes involved in the breaksites of chr15 and chr12 as c-Myc and IgH, respectively. Riccardo Dalla-Favera and his colleagues (39) showed independently that IgH and C-Myc were at the breaksites in the human t(8;14) q32,q24. Similar findings were soon made with the rat immunocytomas. A second type of Ig/C-Myc–like CT that occurs in both humans and mice involves the illegitimate recombination of Ig light-chain loci and a region 3' of c-Myc (called the plasmacytoma variant [PVT-1] locus) (see Table 1). Thus, a family of homologous Ig/C-Myc CTs exists in at least three different mammalian species.
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Cytogenetics of Leukemia: Chimeric Genes and Fusion Proteins 1980–2000 |
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TopAbstractDiscovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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In 1983, the genes at the breaksites in the Philadelphia chromosome were identified as the abl oncogene (chr9) and bcr (chr22) (40). The v-abl oncogene was first isolated from a mouse lymphosarcoma (41). The genetic study of t(9;22) gene and its protein products revealed a new and intriguing phenomenon the two genes at the breaksites had formed a novel chimeric gene with a 5' segment derived from bcr and the 3' segment from human abl that produced a functional protein BCR-ABL. Similar chimeric genes were discovered in acute leukemias (AML, ALL, APL). These include de novo leukemias in adults; childhood leukemia where strong evidence indicates some of these CTs occurred in utero (42,43) and the leukemias that develop in patients who have received chemotherapy (44,45). It is important to note that only a fraction of acute leukemias have a balanced recurring CTs (rCTs).
In a recent compilation, Zhang and Rowley have listed 129 different rCTs in human leukemias (46). Some reduction in the complexity of this large number comes from the finding that in many examples one dominant gene (usually the one controlling the 3' segment of the chimera) may have multiple partners (47). An extreme example are the 47 partners for 11q23 breaksite gene, which has been identified as mixed lineage leukemia (MLL) gene. The mutations generated by rCTs comprise a substantial group of potential oncogenic mutations. Although the promoter insertion of oncogenes was at first an exciting model, because the original oncogenes were "transforming genes," this concept has been modified. The growing list of new rCTs has uncovered new classes of genes that participate in gene transcription and may act as controllers of multiple gene activities and that alter the differentiation and proliferation of hematopoietic cells, eg, MLL, APL (48–50).
The development of polymerase chain reaction (PCR) technology coupled with the knowledge of the DNA sequences contiguous to the breaksites in rCTs made possible an alternative to the standard cytological methods for determining the presence of illegitimate recombinations (IRs) between chromosomes (ie, CTs) (51,52). The sensitivity for detecting the IR was quantitatively increased. This was not without cautions about artifacts created by PCR. The exciting experiments of Limpens and Kluin (53) that the Igh/Bcl-2, t(14;18) CT could be found in healthy individuals (now estimated to be 
80%) raised many questions about the biological significance of IRs and the development of neoplasia. The rCTs provide a clue to the natural history of neoplasia, and they have a definite probability (though in some examples very small) of culminating in the formation of an aggressive neoplastic clone. Each gene with oncogenic potentiality involved in an rCT must be separately evaluated for how it contributes to neoplastic development.
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Factors that Contribute to Chromosomal Instability a Current and Continuing Insight |
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TopAbstractDiscovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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Conceptual advances in other related areas have opened up a vastly complex but interrelated set of mechanisms and responses to DNA damage that are determinants in CT development (54). Most important is the extensive science of DNA repair [for history see (55)]. The DNA double-strand break (DSB) is the critical lesion in CT development and the responses to this damage are concerned with how cells immediately control, ultimately repair, and survive. DSBs may activate cell death by apoptosis or the cells may not survive the loss of the acentric fragments in successive mitoses. The importance of apoptosis as the major mechanism for eliminating damaged genomes and the cells that possess them is revealed by the consequences of abrogating the regulators of apoptosis through mutations of p53 which activates apoptosis (56,57) or by the effects of transgenes that code for anti-apoptotic factors (bcl-2, bcl-xL) (58,59). Both mechanisms dramatically increase and accelerate tumorigenesis.
The immediate response to DNA damage is by patching the broken ends with Ku70/86, 
H2AX and interrupting the cell cycle by ATM, ATR. These actions importantly allow the participation DNA repair enzymes to find, bind, and religate. The major pathways of repair are by homologous recombination and nonhomologous end-joining. Each one of these pathways involves the participation of multiple components (see Figure 1). Deficiencies in many of these components may be associated with increased chromosomal instability and tumor formation [for review see (60)].
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Conclusion |
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TopAbstractDiscovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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The association of CTs as generators of potential oncogenic mutations continues to advance into new vistas and provide insights into the genetic basis of neoplastic development. A brief sketch of the history of CTs and tumors is subjective and must be apologetic for its omissions, but most of all indicate that this is a moving and exciting field.
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TopAbstractDiscovery of Chromosomes in...Chromosomal Translocations and...Boveri's Thoughts on Chromosomes...Cytogenetics in Mammalian Tumor...1975-2000: Consistent Recurring...Oncogenes at Breaksites: The...Cytogenetics of Leukemia:...Factors that Contribute to...ConclusionReferences |
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