to be uncovered (Nathanson and Weber 2001; Ponder 2001). However, epidemiologic evidence is highly suggestive of a more extensive genetic component to breast cancer risk (Peto and Mack 2000), and much effort is being expended to identify the functional gene polymorphisms that might be involved. Although some of the evidence remains controversial, Dunning and colleagues (1999) and Nathanson and Weber (2001) note the potential involvement of polymorphic genes that encode steroid hormone receptors and paracrine growth factors (e.g., AR, CYP19) together with genes involved in the metabolism of chemical species (e.g., GSTP1) and in DNA damage response (e.g., ATM, RAD51, TP53). The most persuasive evidence on breast cancer genes other than BRCA1 and BRCA2 concerns the cell cycle checkpoint kinase gene CHEK2. A truncating germline deletion of this gene is present in around 1% of healthy individuals and is estimated to result in about a twofold increase of breast cancer risk in women and about a tenfold increase in men (Meijers-Heijboer and others 2002). Two data sets have some association with cancer risk after radiation.

First is the question of breast cancer risk in individuals who are heterozygous carriers of the ATM mutation of the highly radiosensitive disorder AT. ATM carriers (ATM+/−) might represent 0.25–1% of the general population, and there is evidence of modestly increased cellular radiosensitivity in ATM+/− genotypes. It is therefore reasonable to consider an increased risk of radiogenic breast cancer in these carriers. Considerable effort has been expended on molecular epidemiologic analysis of spontaneous breast cancer risk in ATM+/− women (Bishop and Hopper 1997; ICRP 1998; Broeks and others 2000; Laake and others 2000; Geoffroy-Perez and others 2001; Olsen and others 2001; Teraoka and others 2001). Although the position remains somewhat uncertain, it seems reasonable to conclude that while increased breast cancer risk may be associated with ATM+/− in some cohorts, the relative risk is likely to be modest (<3), and the overall impact on spontaneous breast cancer risk in the population is rather small. Some data suggest, however, that it is only certain dominant negative missense mutations of ATM that predispose to cancer (Khanna 2000; Chenevix-Trench and others 2002), and for these, the relative risk may be substantially higher. The critical question is whether the ATM+/− genotype may more specifically and significantly increase breast cancer risk after radiation. For good scientific reasons, some early claims on substantial risks at low doses are not regarded as being well founded (see ICRP 1998). While a modestly increased contribution of the ATM+/− genotype to radiogenic cancer risk should not be discounted, three recent studies on patients developing second cancers after RT argue against a major impact from the ATM gene (Nichols and others 1999; Broeks and others 2000; Shafman and others 2000). In total, these studies considered 141 patients with second cancers; the studies of Shafman and colleagues (2000) and Broeks and colleagues (2000) specifically considered a total of 89 second breast cancer cases. None of the cases studied carried ATM mutations.

The second line of evidence concerns the inheritance of chromosomal radiosensitivity and its association with breast cancer risk (Roberts and others 1999). In brief, in studies on cultured blood lymphocytes, up to around 40% of unselected breast cancer cases were shown to exhibit an abnormal excess of chromatid aberrations following X-irradiation in the G2 phase of the cell cycle. By contrast, this chromosomal trait was seen in only around 5% of age-matched controls. Follow-up family studies provided evidence on the heritability of the trait, which, although not of a simple Mendelian form, could be genetically modeled. As yet there is no evidence on the specific genes involved.

In summary, advances in breast cancer genetics do allow the construction of a general scheme to describe the interactive genetic component of familial risk, including some allowance for common genes of low penetrance (Ponder 2001). Polygenic computational models describing the overall genetic component of spontaneous breast cancer risk in the population are also under development (Antoniou and others 2002). Although gene candidates and cellular phenotypes may prove to be instructive, there is at present little to guide specific conclusions on the question of the common genetic component of radiation-associated cancer risk. The evidence available would tend to argue against a major overall impact on radiation breast cancer risk from the ATM gene in its heterozygous form, although specific ATM genotypes may, in principle, carry substantially increased risk.

Human Colonic and Other Neoplasms

There is evidence that the genetic component of colonic cancer also includes a significant contribution from genes of low penetrance. In a recent review of 50 studies on the potential impact of common polymorphisms, Houlston and Tomlinson (2001) identified significant associations with risk for APC-I1307K, HRAS1-VNTR, and MTHFR-Val/Val. For TP53, NAT1, NAT2, GSTM1, GSTT1, and GSTP1 polymorphisms, the evidence was weaker. Specific data relating to gene polymorphisms and radiation risk are lacking although, as for breast cancer, there is some evidence of an association between colon cancer risk and lymphocyte chromosomal radiosensitivity (Baria and others 2001).

Finally, in illustration of ongoing work, it is relevant to mention polymorphic associations between GSTP1 and chemotherapy-related leukemia (Allan and others 2001), MCUL1 and uterine fibroma (Alam and others 2001), GFRalpha1 and medullary thyroid carcinoma (Gimm and others 2001), PPARG and endometrial carcinoma (Smith and others 2001), and TP53 and adrenal cortical carcinoma (Ribeiro and others 2001). In their review of gene-environment interactions, Shields and Harris (2000) focus on lung cancer risk, and in this area, Bennett and colleagues (1999)

The National Academies of Sciences, Engineering, and Medicine
500 Fifth St. N.W. | Washington, D.C. 20001

Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement