Significance of Oncogene Amplifications in Breast Cancer in Atomic Bomb Survivors: Associations with Radiation Exposure and Histological Grade

Abstract

It has been postulated that radiation induces breast cancers in atomic bomb survivors. Oncogene amplification is an important mechanism during breast carcinogenesis and also serves as an indicator of genomic instability (GIN). The aim of this study is to clarify the association of oncogene amplification in breast cancer in atomic bomb survivors with radiation exposure. A total of 593 breast cancers were identifi ed in atomic bomb survivors from 1968 to 1999, and the association between breast cancer incidence and atomic bomb radiation was evaluated. Invasive ductal cancers from 67 survivors and 30 nonsurvivors were analyzed for amplification of the HER2 and c-Myc genes by fl uorescence in situ hybridization and expression of hormone receptors by immunostaining. The incidence rate signifi cantly increased as exposure distance decreased from the hypocenter [hazard ratio (HR) per 1.0-km decrement, 1.47; 95% confi dence interval (CI), 1.30-1.66]. The incidence of HER2 and c-Myc amplification was significantly increased in the order of control, distal, and proximal groups (P=?0.0238 and 0.0128, respectively). Multivariate analyses revealed that distance was a risk factor for co-amplification of HER2 and c-Myc in breast cancer in survivors (odds ratio per 1.0-km increment, 0.17; 95% CI, 0.01-0.63]. The histological grading of breast cancers became signifi cantly higher in the order of control, distal, and proximal groups, and was associated with oncogene amplifications. This study suggested that atomic bomb radiation may affect the development of oncogene amplification by inducing GIN and may be associated with a higher histological grade in breast cancer found in survivors.