Abstract: Publisher Summary This chapter discusses the myc /IgH translocation. It considers the nature of the variant forms of the plasmacytoma and Burkitt translocations. The bcr–abl recombination that creates the Philadelphia chromosome is also described and its role in the development of chronic myeloid leukemia is considered. Three putative oncogenes— pvt-1, bcl-1, and bcE-2 —have been identified at the translocation junctions in lymphoid tumors by the molecular cloning of “aberrant” immunoglobulin gene rearrangements. Several other chromosomal abnormalities specific to particular lymphoid and myeloid neoplasms are assessed in the chapter for the possible involvement of oncogenes. The challenge for the future is not only to delineate the molecular basis for other translocations but also to identify the normal function of the genes involved. The frequent association of abnormalities involving band 11q23 in acute leukemias with monocytic differentiation suggests that they involve the alteration of a gene important in myelomonocytic differentiation. The recent localization of the metallothionein gene cluster to the band q22 of chromosome 16 raises intriguing questions regarding the chromosome abnormalities associated with acute myelomonocytic leukemia (AMML).

Abstract: Publisher Summary This chapter discusses the epidemiology and early diagnosis of primary liver cancer in China. Epidemiological studies in different areas in China have revealed several outstanding risk factors of primary liver cancer (PLC)—that is, the hepatitis B virus (HBV) infection, pollution of drinking water, contamination of food by AFB 1 and/or nitrosamines, and family predisposition. Accordingly, a program of HBV vaccination, improved supply of drinking water, better preservation and storage of food, and possibly chemoprevention for high-risk populations should be effective preventive measures. Newer means for the localization of small-size PLC (under 5 cm), such as type B ultrasonography, nuclide scanning, computerized tomography, and hepatoangiography, represent remarkable progress in improving markedly the success of surgery and, hence, the survival rate of PLC patients. Studies have shown that frequent AFP screening in high-risk populations is highly recommended to detect early cases of PLC. The advances in the knowledge of PLC have been encouraging; however, much work remains to be done on the etiological agents and the mechanism of oncogenesis.

Abstract: Publisher Summary Literature pertaining to the genetic epidemiological studies of familial cancer has been reviewed from a historical perspective. During the early twentieth century, developments in the fields of genetics, statistics, and epidemiology provided concepts and methods that permitted investigators to recognize important deficiencies in past studies, and to design others in which the critical comparisons could be made between patient groups and control groups. Registries of cancer incidence in large populations became available in several countries in the middle 20th century providing a standard “control group” for comparison. Large surveys of site-specific cancer experience in families, rigorously designed and analyzed, found for most kinds of cancers a two- to threefold increased risk for close relatives of propositi. These studies also re-emphasized the great difficulty in obtaining even minimally complete family health history information and the importance of verifying all reported cases with medical or vital records. Segregation and linkage analysis and their present applications to family studies of cancer were also reviewed. As a result of the increasing number of DNA polymorphisms that are becoming available due to the developments in molecular biology, the human gene map can be expected to be well defined in the near future, and investigation of families using segregation and linkage analysis will then be instrumental in defining the role of heredity in the development of cancer in human populations.

Abstract: Publisher Summary This chapter presents some of the biological investigations that discuss the position of terminal deoxynucleotidyltransferase (TdT) in the normal hematopoietic system and the use of TdT determination in leukemia research. It covers the methodology used in TdT research and the use of TdT determinations in clinical diagnosis. The basic biological findings provide some deeper understanding of the participation of TdT+ cells in the malignant process. It is of considerable utility to use TdT as a marker for differential diagnosis of acute leukemias, but whether the presence of expanded populations of this kind contributes to the disease process, or will provide leverage for therapy, remains to be determined. The fact that cells may express antigens in an aberrant manner is of descriptive interest, but whether aberration has deleterious effects on the cells still is not known. Resolution of these questions should lead deeper into the mechanisms of differentiation in cellular and humoral immunity. Currently, TdT is the only protein that leads to this junction. Tracing this system through its evolutionary origins might lead to the true roots of the immune systems of the higher vertebrates.

Abstract: Publisher Summary This chapter reviews the current state of information available on the tumorigenesis in Xiphophorus and review the strategies to which the identification of genetic loci in malignancy is owed. Neoplastic growth is a widespread developmental aberration among multicellular organisms ranging from primitive avertebrates, such as coelenterates and annelids, to man. A major goal of the studies concerning neoplasia has been to obtain insight into its cellular and molecular basis, and it has been suggested that cellular genes are paramount in the etiology of neoplasia. The high degree of evolutionary conservation of the proto-oncogenes points to the basic functions that these genes normally might have for the cell and at the same time indicates that crucial steps associated with tumorigenesis might take similar pathways in different classes of vertebrates. There are now four main lines of molecular evidence that relate cellular genes to neoplasia: (1) insertional mutagenesis or chromosomal rearrangement, (2) gene amplification, (3) structural alteration of a cellular gene itself that results in the synthesis of an altered protein, and (4) generation of fusion genes as a result of gene translocation with possibly altered biological activities. Genetic mechanisms that are operative in the development of tumors of genetic origin in Xiphophorus remains to be addressed in future experiments.

Abstract: Publisher Summary The mechanisms by which certain genes can alter the growth regulation of cells and lead to transformation to the oncogenic state are of great importance. One class of oncogenes comprises of viral genes that have the ability to immortalize certain primary cells and, in combination with various other oncogenes, elicit the fully transformed phenotype. In many instances, these immortalizing genes have been shown to function as transcriptional regulatory genes during lytic viral infection. The direct evidence for the role of transcription activation in oncogenesis is lacking, but a variety of indirect evidence has suggested that this may be a contributing factor. In addition, the study of these genes, apart from their role in oncogenesis, has provided valuable insight into the mechanisms of transcription control. This chapter focuses on these two subjects: current understanding of the way such genes control transcription initiation and the possible involvement of such a mechanism in oncogenesis. The first issue is conceptually straightforward although experimentally difficult. The resolution of the mechanisms requires the isolation of the proteins involved and an analysis of their nature before and after transcriptional induction. The second issue is more complex and likely will never be fully resolved.

Abstract: Publisher Summary This chapter summarizes the third mechanism of oncogene activation—oncogene amplification. It illustrates the various ways by which the oncogenic potential of different proto-oncogenes can be activated. Because of the involvement of myc oncogenes in amplifications in a variety of tumors, other lesions that also activate the cellular oncogene c-myc and the aspects of the normal regulation of this oncogene are also described. Since its discovery in drug-resistant eukaryotic cells, somatic amplification of specific genes has been implicated in an increasing variety of adaptive responses of cells to environmental stresses. Experimental work on drug-resistant cells has shown that in the absence of a selection pressure (drug), double minute chromosomes (DMINs) and the amplified genes that they contain are lost, whereas amplified DNA in the form of homogeneously staining regions (HSRs) is retained in the cells. If DMINs and HSRs contain amplified genes that encode drug-resistant or growth-stimulating protein products, it would follow that the more stable chromosomal form, the HSR, confers a greater selective growth advantage for cells. Although DMINs and HSRs have been described predominantly in tumor cells selected for the resistance to cytotoxic drugs, it is also clear that DMINs and HSRs may be present in cancer cells before the start of therapy.

Abstract: Publisher Summary This chapter discusses the biochemistry and the molecular genetics of a particular set of oncogenes, originally identified as transforming genes of avian acute leukemia viruses. This group of retroviruses played a key role in establishing the concept that normal cells contain multiple genes with the potential to become dominant oncogenic determinants. Six different cell-derived oncogenes were identified in this virus group alone, myc oncogene among them— by now one of the most intensively studied genes implicated in viral and nonviral carcinogenesis. In addition, several basic features and some unique variations of oncogene structure and expression were first diagnosed in this virus group. Also, a crucial progress in the search for physiological functions of cellular alleles of oncogenes was achieved by the discovery of close sequence homology between an oncogene of an avian acute leukemia virus and a human gene encoding a growth factor receptor, Hence, the oncogenes of avian acute leukemia viruses serve in the chapter as a model case to review the current knowledge about the structure and function of eukaryotic genes involved in malignant cell transformation.