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Breast cancer risk and possible mechanisms of radiation-induced genomic instability in the Swedish hemangioma cohort

Female breast cancer is one of the most frequent cancers worldwide. Knowledge on breast cancer risk after exposure with ionizing radiation is mainly based on the atomic bomb survivors. However, since Western background breast cancer rates are about a factor 2-3 higher, the Swedish hemangioma cohort provides a unique opportunity for independent assessment of radiation-induced breast cancer risk, and for risk transfer between populations.

17,200 female Swedish hemangioma patients, who had been exposed to ionizing radiation because of skin hemangioma, were analyzed for breast cancer incidence with descriptive excess relative risk models and mechanistic models of carcinogenesis. The dosimetry system has recently been updated, leading to substantially reduced doses for a part of the most highly exposed women. In total, 877 breast cancer cases were reported until 2009. A characteristic property of the cohort is the very young exposure at infant age.

Explicit mechanistic models incorporating effects of genomic instability (GI) were developed and applied to the hemangioma cohort. It was found that a radiation-induced transition towards GI was highly significant. The models indicate that the main effect of radiation-induced GI is to increase the rate of transition of non-initiated cells to initiated cells with a proliferative advantage. This indicates, at least for exposure at young ages, that radiation-induced cellular changes might activate different molecular pathways than spontaneous mutations, leading to longer-term processes.

Fig. 1: Mechanistic model of carcinogenesis with path of genomic instability (GI). Radiation induces a transition towards GI, σ0 = r x d, with dose rate d. In the GI pathway the rates of transitions to cells with a proliferative advantage are enhanced, ν0, GI >> ν0.

As a consequence of the re-evaluation of the dosimetry system, the risk estimates increased by a factor of 2 compared to previous analyses of the cohort, with an excess relative and absolute risk of 0.48 Gy−1 (95% CI 0.28; 0.69) and 10.4 (104 PYR Gy)−1 (95% CI 6.1; 14.4), respectively. The agreement between the descriptive ERR model and mechanistic models implementing effects of a potential radiation-induced GI is very good.

Fig. 2: Excess relative risk per dose as a function of age (with 68% CI for ERR model) for different models. The agreement between all best models is very good. A standard mechanistic model without effects of a potential radiation-induced GI (TSCE-direct) is strong disfavoured from quality of fit.

 

Publication:  M. Eidemüller, E. Holmberg, P. Jacob, M. Lundell and P. Karlsson, Breast cancer risk and possible mechanisms of radiation-induced genomic instability in the Swedish hemangioma cohort after reanalyzed dosimetry, Mutation Research 775 (2015) 1-9. (Open Access: PDF, DOI Link)

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