Newsfeed display by CaRP Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear. In a case report of a family with multiple cases of breast cancer in a single generation, the cancers were associated with repeated fluoroscopic exposure in childhood.

Lymphocytes from affected family members demonstrated reduced efficiency of repair of x-ray-induced DNA breaks, suggesting that the breast cancers could have resulted from a genetic susceptibility to the mutagenic effect of radiation exposure. A small follow-up study found evidence of suboptimal repair of x-ray-induced DNA breaks in 12 of 17 women at increased breast cancer risk due to a positive family history, compared with 6 of 19 control subjects (OR 5.2; 95% CI, 1.04-28.57).

In vitro studies of BRCA1 and BRCA2 function suggest a possible role for these genes in repair of x-ray-induced DNA damage. Human cancer cells containing mutated BRCA1 are hypersensitive to ionizing radiation via transcription-coupled DNA repair mechanisms.

While human tumor cells deficient in the BRCA2 protein also demonstrate deficiencies in the repair of radiation-induced DNA breaks, cells that carry a single mutated copy of BRCA2 have normal repair. These preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 and BRCA2 mutations. Since BRCA1/2 mutation carriers are heterozygotes, however, radiation sensitivity might occur only after a somatic mutation has damaged the normal copy of the gene.

Increased sensitivity to radiation has also been postulated as a source of increased breast cancer risk among carriers of mutations in the ATM gene.

Radiation sensitivity has also been reported in Li-Fraumeni syndrome (LFS) and is associated with a greatly increased rate of multiple primary malignancies in persons with this disorder (57% cumulative probability of second malignancy 30 years after diagnosis of a first cancer). Breast cancer is the most common tumor in LFS families, occurring at an average age of 37 years.

The possibility that genetic susceptibility to breast cancer occurs via a mechanism of radiation sensitivity raises questions about radiation exposure. It is possible that diagnostic radiation exposure, including mammography, poses more risk in genetically susceptible women than in women of average risk. Therapeutic radiation could also pose carcinogenic risk. A cohort study of BRCA1 and BRCA2 mutation carriers treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of mutation carriers.
Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Empiric data are needed to address these questions.