on radiation cancer risk (ICRP 1998). Relevant data on genetic susceptibility to cancer are reviewed in the final section of this chapter, and some interim judgments are developed about their implications for radiation cancer risk in the population.


Gene and Chromosomal Mutations in Spontaneously Arising Human Tumors

Studies on the cellular and molecular mechanisms of tumorigenesis have in recent years cast much light on the complex multistep processes of tumorigenesis and its variation among tumor types. There is a vast literature on tumor biology and genetics (Bishop 1991; Loeb 1991, 1994; Hartwell 1992; Levine 1993; Vogelstein and Kinzler 1993; Hinds and Weinberg 1994; Weinberg 1994; Boland and others 1995; Karp and Broder 1995; Levine and Broach 1995; Skuse and Ludlow 1995; Kinzler and Vogelstein 1998; Rabes and others 2000; Khanna and Jackson 2001; Balmain and others 2003), and it is sufficient to highlight the principal points of current fundamental knowledge that may serve to guide judgments on the impact of ionizing radiation on cancer risk.

Tumor development is generally viewed as a multistep clonal process of cellular evolution that may be conveniently but imprecisely divided into a number of overlapping phases: (1) tumor initiation, which represents the entry via mutation of a given normal somatic cell into a potentially neoplastic pathway of aberrant development; cellular targets for this process are generally held to have stem cell-like properties; (2) tumor promotion, which may now be viewed as the early clonal development of an initiated cell; cell-cell communication, mitogenic stimulation, cellular differentiating factors, and mutational and nonmutational (epigenetic) processes may all play a role in this early pre-neoplastic growth phase; (3) malignant conversion, which represents the tumorigenic phase where the evolving clonal population of cells becomes increasingly committed to malignant development; mutation of genes that control genomic stability is believed to be particularly important; and (4) malignant progression, which is itself multifaceted, is a relatively late tumorigenic phase during which neoplastic cells become increasingly autonomous and gain a capacity for invasion of surrounding normal tissue and spread to distant sites (metastasis); the development of tumor vasculature is important for the development of solid cancers (Folkman 1995). In addition, there is evidence that inflammatory processes and the microenvironment in which tumors develop are important cofactors for malignant progression (Coussens and Werb 2002). Overall, it is clear that only a small fraction of cells that enter tumorigenic pathways complete the above sequence that results in overt malignancy (Rabes and others 2000), and that the whole process can take many years.

The balance of evidence suggests that sequential gene and chromosomal mutations act as the principal driving force for tumorigenic development, with phase transitions being dependent on the selection and overgrowth of clonal neoplastic variants best fitted for the prevailing in vivo conditions. Although there are exceptions, the consensus view is that tumor initiation or promotion is a monoclonal process having its origin in the appearance of a single aberrant cell (Levy and others 1994; Rabes and others 2000).

The tumor initiation phase is most difficult to study directly, but in recent years it has become evident that a relatively tissue-specific set of so-called gatekeeper genes (Kinzler and Vogelstein 1997; Lengauer and others 1998) may be critical mutational targets for cellular entry into neoplastic pathways. Table 3-1 provides examples of such genes and their principal associated neoplasms. These gatekeepers are frequently involved in intracellular biochemical signaling pathways, often via transcriptional control, and are subject primarily to productive loss-of-function mutations. They fall into the tumor-suppressor gene category consistent with the germline role of many of these genes in autosomal dominant familial cancer (see “Genetic Susceptibility to Radiation-Induced Cancer,” later in this chapter). The somatic loss of function associated with gatekeeper gene inactivation can arise by point mutation (often of the chain-terminating type), intragenic deletion, or gross chromosomal loss events (Sidransky 1996; Kinzler and Vogelstein 1997, 1998). For some genes, epigenetic silencing events may also be important (Jones and others 1992; Feinberg 1993, 2004; Ranier and others 1993; Merlo and others 1995; Issa and Baylin 1996; Roth 1996).

It is evident from Table 3-1 that the gatekeeper gene hypothesis applies principally to the genesis of solid tumors. For lymphomas and leukemia a somewhat different mechanism appears to apply. In these neoplasms, the early productive events often involve chromosomally mediated gain-of-function mutations in tissue-specific proto-oncogenes (i.e., gene activation or intragenic fusion involving juxtaposition of DNA sequences by specific chromosomal exchange; Rabbitts 1994; Greaves and Wiemels 2003). In many instances, these leukemia- or lymphoma-associated chromosomal events involve the DNA sequences (TCR [T cell receptor] and IG [immunoglobin]) involved in immunological

TABLE 3-1 Examples of Human Tumor-Suppressor Genes of the Gatekeeper Type


Principal Cancer Type

Mode of Action


Colon carcinoma

Transcriptonal regulator





Kidney carcinoma

Transcriptional regulator



Transcription factor


Skin (basal cell)

Signaling protein

NOTE: GTPase = guanosine 5′-triphosphatase.

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