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Cancer is a heritable disorder of somatic cells. Carcinogenesis at the cellular level is like an opened Japanese fan, because initiated cells grow in several directions and tumors suggest the edge of the fan by having many gene abnormalities. We discuss here the primal force and gene networks (federal headship) in renal carcinogenesis. The Eker ( Tsc2 mutant) rat model of hereditary renal carcinoma (RC) is an example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Recently, we discovered a new hereditary renal carcinoma in the rat in Japan, and the rat was named the “Nihon” rat. We suggest that its predisposing ( Bhd ) gene is a novel renal tumor suppressor gene. We present these unique models as part of the study of problems in carcinogenesis; e.g., multistep carcinogenesis, cancer prevention and the development of the therapeutic treatments that can be translated to human patients, as well as how environmental factors interact with cancer susceptibility gene(s).

Ionizing radiation is perhaps the most extensively studied human carcinogen. There have been a number of epidemiological studies on human populations exposed to radiation for medical or occupational reasons, as a result of protracted environmental exposures due to radiation accidents, or after atomic bombings. As a result of these studies exposure to ionizing radiation has been unambiguously linked to cancer causation. While cancer induction is the primary concern and the most important somatic effect of exposure to ionizing radiation, potential health risks do not only involve neoplastic diseases but also somatic mutations that might contribute to birth defects and ocular maladies, and heritable mutations that might impact on disease risks in future generations. Consequantly it is important we understand the long-term health risks associated with exposure to ionizing radiation.

Genetic, or genomic, instability refers to a series of observed spontaneous genetic changes occurring at an accelerated rate in cell populations derived from the same ancestral precursor. This is far from a new finding, but is one that has increasingly gained more attention in the last decade due to its plausible role(s) in tumorigenesis. The majority of genetic alterations contributing to the malignant transformation are seen in growth regulatory genes, and in genes involved in cell cycle progression and arrest. Genomic instability may present itself through alterations in the length of short repeat stretches of coding and non-coding DNA, resulting in microsatellite instability. Tumors with such profiles are referred to as exhibiting a mutator phenotype, which is largely a consequence of inactivating mutations in DNA damage repair genes. Genomic instability may also, and most commonly, results from gross chromosomal changes, such as translocations or amplifications, which lead to chromosomal instability. Telomere length and telomerase activity, important in maintaining chromosomal structure and in regulating a normal cell’s lifespan, have been shown to have a function in both suppressing and facilitating malignant transformation. In addition to such direct sequence and structural changes, gene silencing through the hypermethylation of promoter regions, or increased gene expression through the hypomethylation of such regions, together, form an alternative, epigenetic mechanism leading to instability. Emerging evidence also suggests that dietary and environmental agents can further modulate the contribution of genetic instability to tumorigenesis. Currently, there is still much debate over the distinct classes of genomic instability and their specific roles in the initiation of tumor formation, as well as in the progressive transition to a cancerous state. This review examines the various molecular mechanisms that result in this genomic instability and the potential contribution of the latter to human carcinogenesis.

Intensive research efforts during the last several decades have increased our understanding of carcinogenesis, and have identified a genetic basis for the multi-step process of cancer development. Tumors grow through a process of clonal expansion driven by mutation. Several forms of molecular alteration have been described in human cancers, and these can be generally classified as chromosomal abnormalities and nucleotide sequence abnormalities. Most cancer cells display a phenotype characterized by genomic hypermutability, suggesting that genomic instability may precede the acquisition of transforming mutations in critical target genes. Reduced to its essence, cancer is a disease of abnormal gene expression, and these genetic abnormalities contribute to cancer pathogenesis through inactivation of negative mediators of cell proliferation (including tumor suppressor genes) and activation of positive mediators of cell proliferation (including proto-oncogenes). In several human tumor systems, specific genetic alterations have been shown to correlate with well-defined histopathological stages of tumor development and progression. Although the significance of mutations to the etiological mechanisms of tumor development has been debated, a causal role for such genetic lesions is now commonly accepted for most human cancers. Thus, genetic lesions represent an integral part of the processes of neoplastic transformation, tumorigenesis, and tumor progression, and as such represent potentially valuable markers for cancer detection and staging.

Epigenetic mechanisms are involved in critical nuclear processes such as transcriptional control, genome stability, replication and repair. Recent evidence suggests that changes in the epigenetic repertoire can drive tumorigenesis. This review examines the latest experimental evidence that questions the mechanisms underlying the consequence of epigenetic changes in gene regulation and cancer development.