Breast cancer: Genetic predisposition and exposure to radiation

Abstract

The identification of breast cancer susceptibility genes, such as BRCA1, BRCA2, ATM, and p53, has been accompanied by the examination of the effects of radiation in combination with genetic mutations at these loci. Women at high risk for developing breast cancer may respond differently than the general population to low- and high-dose radiation exposures associated with screening and treatment. Epidemiologic studies are being performed to investigate the effects of radiation on subsequent breast cancer development in genetically predisposed individuals. Mouse strains with specific genetic modifications are being created to study the consequence of both inherited mutations and radiation on mammary gland carcinogenesis. Finally, studies investigating DNA damage-response pathways after radiation exposure are being performed. Recent work on the effects of several known or suspected breast cancer susceptibility genes, alone or in combination with radiation, is presented here, and directions for future research are considered.

The spectrum of ATM missense variants and their contribution to contralateral breast cancer

“…Candidate-genes like ATM are implicated in maintenance of genome integrity. Their involvements in breast cancer susceptibility as well as their role in DNA-damage repair signalling make them excellent candidates for a role in radiation-induced breast cancer [ 21 ]. Recently, we showed that women with a pathogenic germline mutation in a DNA repair pathway gene (e.g.…”

Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation

“…There are two sources of iatrogenic IR to which carriers of BRCA2 mutation are commonly exposed: screening mammography and radiation therapy used as an adjuvant to breast 'wide local excision'. Annual mammography is currently advised from the age of 25 or 10 years before the index case (Burke et al, 1997), and concern has been raised about the effect this may have on somatic mutation induction (Bennett, 1999;Friedenson, 2001). In the absence of alternatives to mammographic screening, the benefits of early detection of an occult breast cancer probably outweigh the increased risk of radiation-induced mutagenesis.…”

Identification of mammary carcinogens in rodent bioassays

“…In addition, the numerous transgenic and gene-targeted models, which have been developed to study mammary gland carcinogenesis or to model the inheritance of human breast cancer susceptibility genes, may be useful for identifying mammary gland carcinogens. These models have been well described and reviewed elsewhere [Bennett, 1999;Xu et al, 1999;Hutchinson and Muller, 2000;Siegel et al, 2000;Ludwig et al, 2001].…”