degree of spontaneous tumor risk that is imposed must be sufficient to distinguish that family from others that are noncarriers. Given that, on average, spontaneous cancer incidence in the general population is around 30%, the information currently available is restricted largely to mutations where the cancer in question is expressed at a high relative frequency in gene carriers (i.e., so-called high-penetrance mutations).
Other features of importance are (1) the organ specificity of many cancer-predisposing mutations, (2) the age of onset of given neoplasms in gene carriers that usually occurs at younger ages than in noncarriers, (3) the frequent occurrence of multiple tumors in gene carriers, and (4) the substantial variation for cancer risk between carriers of a given gene mutation, suggestive of major influences from the genetic background and/or life-style of the host. These issues of heritable cancer risk have been summarized by the International Commission on Radiological Proterction (ICRP 1998) and more recently by Ponder (2001). The crucial point, to be developed later, is that current knowledge of heritable cancer susceptibility in humans is restricted largely to relatively rare mutations of high penetrance. Cancer may be regarded as a multifactorial disorder (see Chapter 4), and genetic views developed from the study of other multifactorial conditions, such as coronary heart disease, suggest strongly that there will be many more variant cancer genes having lower penetrance than those listed in Tables 3-1 and 3-2. The current lack of knowledge about the nature, frequency, and impact of such genes imposes fundamental limitations in respect of the objectives stated earlier.
In making judgments on the radiation response of cancer-prone individuals it is valuable to consider first the theoretical expectations that follow from current knowledge of the cellular mechanisms that are likely to be involved in cancer susceptibility. Germline mutations in DNA damage response or repair genes, tumor-suppressor genes, and proto-oncogenes are considered in turn.
As outlined in Chapters 1 and 2, different forms of DNA damage are recognized and processed in mammalian cells by different biochemical pathways, which share few genetic determinants. Accordingly, there is no expectation of a global association between DNA damage response or repair deficiency and sensitivity to the tumorigenic effects of radiation. Rather, the expectation is that a deficiency of genes associated with recognition or repair of the form of damage that is critical for cellular response to radiation (i.e., DNA DSB) will be of greatest significance for radiation cancer risk. On this basis the autosomal recessive disorders AT and NBS in Table 3-3 might be judged to exhibit increased cancer risk after ionizing radiation, whereas XP would not. Stated simply, germline deficiency in the recognition and/or repair of induced DNA damage of specific forms is expected to increase the abundance of genome-wide damage in the somatic cells of body tissues. This increased mutational load will tend to increase cancer risk, albeit with differing degrees of expression among tissues. It is important to recognize, however, that a number of autosomal dominant conditions, particularly Li-Fraumeni syndrome (TP53+/−), are determined by genes that play more general roles in the control of stress responses, apoptosis, and/or coordination of the cell reproductive cycle (Chapter 2). Abnormal cellular response or cancer risk in such disorders might be expected for a range of DNA-damaging agents including ionizing radiation.
For tumor-suppressor genes such as VHL and NF1 in Table 3-4 there is no specific association with DNA damage response or repair. Accordingly there is no expectation of increased genome-wide sensitivity to the mutagenic effects of radiation. In these instances increased radiation cancer risk may be anticipated on the basis of the now well-supported hypothesis of Knudson (1986). In brief, there is good evidence that many tumor-suppressor type genes act as tissue-specific gatekeepers to neoplastic pathways (Kinzler and Vogelstein 1997). Since loss or mutation of both autosomal copies of such genes from single cells is believed to be rate limiting for the initiation of neoplastic development, tumor initiation in normal individuals is expected to be a rare cellular event.
A carrier of a germline mutation in a given tumor-suppressor gene will however show loss of function of one such gene copy, thus “unshielding” the second copy in all target somatic cells. The lifetime risk of spontaneous loss or mutation of that second copy from any given population of target cells will be relatively high—hence the often dramatic increase in organ-specific cancer risk.
There is also a clear expectation that exposure of the carrier individual to ionizing radiation or indeed other genotoxic carcinogens would, via the same genetic-somatic mechanism, result in a greater-than-normal risk of organ-specific cancer. Stated simply, the enhanced radiation cancer risk in the carrier individual would be driven by a reduction in the target gene number from two to one; in a given disorder the organs at increased risk would tend to be the same as those involved in spontaneous neoplasia.
There are few well-characterized germline, gain-of-function mutations in proto-oncogenes that have unambiguous associations with cancer risk; a series of characterized ret gene mutations are however known to increase the risk of