. "3 Radiation-Induced Cancer: Mechanisms, Quantitative Experimental Studies and the Role of Genetic Factors." Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2. Washington, DC: The National Academies Press, 2006.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2
response (Rabbitts 1994). Tumorigenic chromosomal exchange events are less well characterized in solid tumors but do occur in certain sarcomas and in thyroid tumors (Rabbitts 1994; Mitelman and others 1997). However, in accord with data from solid tumors, gene deletion and other loss-of-function mutations are not uncommon in lymphohemopoietic tumors (Rabbitts 1994; Mitelman and others 1997).
In relation to tumorigenesis in general, a second broad category of so-called caretaker genes has also been identified, although it is important to stress that the distinction between gatekeeper and caretaker genes is somewhat artificial—there are examples of genes that fulfill both criteria. Caretaker genes are those that play roles in the maintenance of genomic integrity (Kinzler and Vogelstein 1997, 1998). Table 3-2 provides examples of such tumor genes and their associated neoplasms. In such cases, mutational loss of function can lead to deficiency in DNA damage response and repair, repair or recombination, chromosomal segregation, cell cycle control, and/or apoptotic response (Loeb 1991; Hartwell and others 1994; Fishel and Kolodner 1995; Kinzler and Vogelstein 1996, 1998). Almost irrespective of the specific nature of the tumor gene in question, the net result of caretaker gene mutation is to elevate the frequency of gene or chromosomal mutations in the evolving neoplastic clone, and there is evidence that in some tumors this phenotype can arise at a relatively early point in neoplastic growth (Schmutte and Fishel 1999). This increased mutation frequency can be seen to provide the high level of dynamic clonal heterogeneity characteristic of tumorigenesis, thereby facilitating the selection of cellular variants that have gained
TABLE 3-2 Examples of Human Tumor Genes of the Caretaker Type
Principal Cancer Type
Mode of Action
Transcription factor (DNA damage response)
PI-3 kinase (DNA damage response)
MSH2, MLH1, PMS
Colon or endometrial carcinoma
DNA mismatch repair
Breast or ovarian carcinoma
Transcription factor (DNA damage response)
Squamous, basal cell carcinoma, melanoma
Nucleotide excision repair
Familial adenomatous polyposis in families that lack the inherited mutation in the APC gene
Removes adenines misincorporated opposite the mutagenic lesion 8-oxoguanine
the capacity to evade or tolerate antitumorigenic defenses (Tomlinson and Bodmer 1999). These defenses would include cell-cell communication, apoptosis, terminal differentiation, cell senescence, and immune recognition (Rabes and others 2000). Gene and chromosomal mutations conferring enhanced tumor cell survival or growth characteristics have been identified in a range of malignancies (Greenblatt and others 1994; Branch and others 1995; Kinzler and Vogelstein 1998; Greider 1996; Orkin 1996).
In summary, gene and chromosomal mutations of the general types induced by ionizing radiation are known to play a role throughout the multistep development of tumors. Loss of function of gatekeeper genes may be of particular importance in the initiation of common solid tumors, while gain-of-function chromosomal exchanges and gene loss events can arise early in lymphoma and leukemia. The relatively early spontaneous development of genomic instability via specific mutation of caretaker genes is believed to be important for tumorigenesis in many tissues, but epigenetic gene silencing or activation events have also been characterized. The emphasis placed here on early events in tumorigenesis derives from the prevailing view from epidemiologic and animal studies that ionizing radiation acts pri.cipally as a tumor-initiating agent.
Mechanisms of Radiation Tumorigenesis
Data from quantitative animal tumorigenesis (UNSCEAR 1988; Rabes and others 2000) and human epidemiologic studies (UNSCEAR 1994) imply that low-LET (linear energy transfer) ionizing radiation acts principally as a tumor-initiating agent. Specifically, in humans and animals, single acute doses of low-LET radiation produce a dose-dependent increase in cancer risk with evidence that chronic and fractionated exposures usually decrease that risk. Also, experimental animal data show that radiation only weakly promotes the development of chemically initiated tumors, and the generally greater tumorigenic sensitivity of humans to acute irradiation at young ages is more consistent with effects on tumor initiation than with promotional effects that accelerate the development of preexisting neoplasms.
In this section, molecular and cytogenetic data on radiation-associated human and animal tumors are summarized in the context of the mutagenic and tumorigenic mechanisms discussed previously. Particular attention is given to the proposition, based on somatic mutagenesis data, that early arising, radiation-associated events in tumors will tend to take the form of specific gene or chromosomal deletions or rearrangements.
Gene and Chromosomal Mutations in Radiation-Associated Human Tumors
The acquisition of data on TP53 tumor-suppressor gene mutational spectra in human tumors associated with ultra-