TABLE 3-5 Radiation Response and Tumorigenesis in Rodent Homologues of Cancer-Prone Human Genetic Disorders

Genotype

Human Homologue

Radiation Response

Comment

Key References

Early response

Tumorigenesis

Mouse

Atm/

Ataxia-telangiectasia (AT)

Radiosensitive in vivo or in vitro

May be dependent upon Atm genotype (see text)

Defects in meiosis, immunity, and behavior

Barlow and others (1996)

Elson and others (1996)

Xu and others (1996)

Mouse

Brcal/

BRCA+/−

Heritable breast cancer in heterozygotes

Cellular and embryonic radiosensitivity

No published study identified

Embryolethal; association with Rad51/ phenotype

Gowen and others (1998)

Sharan and others (1997)

Mizuta and others(1997)

Connor and others (1997)

Mouse

Tp53+/−

Li-Fraumeni syndrome (LFS)

Excess aneuploidy and G2/M checkpoint defect in bone marrow cells

Highly sensitive to induction of lymphoma or sarcoma

Tumorigenesis associated with loss of Tp53+

Kemp and others (1994)

Bouffler and others (1995)

Mouse

Apc+/−

Familial adenomatous polyposis

None reported

Highly sensitive to induction of intestinal adenoma (breast and other cancers in some genetic backgrounds)

Tumorigenesis associated with loss of Apc+ and other loci

Luongo and Dove (1996)

Ellender and others (1997)

van der Houven van Oordt and others (1999)

Haines and others (2000)

Mouse

Ptch+/−

Nevoid basal cell carcinoma syndrome

Some evidence of cellular radiosensitivity

Sensitive to induction of medulloblastoma

Tumorigenesis associated with loss of Ptch+

Hahn and others (1998)

Pazzaglia and others (2002)

Rat

Tsc2+/−

Tuberous sclerosis

None reported

Sensitive to induction of renal neoplasia

Tumorigenesis associated with loss of Tsc2+

Hino and others (1993, 2002)

genes by germline mutation will lead to a significant increase in individual susceptibility to radiation tumorigenesis. Critical mechanistic support for this hypothesis has been provided by molecular analysis of tumors arising in irradiated Tp53+/−, Apc+/−, and Ptch+/− mice and Tsc-2+/− rats; as predicted, such analyses strongly suggest that radiation acts by inactivating the wild-type tumor-suppressor gene copy in target somatic cells. These wild-type genes appear to be mutated by radiation through mechanisms principally involving substantial DNA loss events, although there are examples of whole chromosome losses as well as intragenic deletions and point mutations.

Although the above studies provide proof-of-principle experimental evidence of strong genetic effects on radiation tumorigenesis in mammalian species, quantification of the genetically imposed radiation risk is most problematical. An ICRP (1998) Task Group, in reviewing much of the data of Table 3-5, suggested that radiation tumor risk in such suppressor-suppressor gene-deficient mice might be elevated by up to a hundredfold or more but cautioned against firm judgments because of (1) problems associated with experimental design and (2) preliminary evidence that natural variation in the genetic background of host animals can have major modifying effects on tumor yield.

During the last few years the impact of such modifier genes on the expression of tumorigenesis in mice has been demonstrated more clearly (Balmain and Nagase 1998). The principal message from this experimental work is that because of the strongly modifying effects of genetic background, rodent homologues are unlikely to provide a quantitatively reliable representation of radiation tumorigenesis in cancer-prone human genetic disorders. Such genetic modification is to be expected in humans, but the specific nature and impact of the modifier genes are likely to differ among species. The issue of genetic modification of radiation response is considered further in the section of this chapter that deals with cancer-predisposing mutations of low penetrance.

Human Data on Radiosensitivity and Tumorigenesis

As noted earlier in this chapter unambiguous evidence of human genetic disorders showing hypersensitivity to tissue injury after radiation is confined to AT and NBS, where conventional radiotherapy procedures have proved disastrous to patients. Adverse, but less profound, reactions to radiotherapy are however reported to occur in around 5% of cancer patients (Burnet and others 1998). Studies on in vitro



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