Abstract
Breast cancer, with a high average excess relative risk (ERR), is considered to be a highly radiogenic tumor-type among A-bomb survivors. Furthermore, the ERR of the early-onset cases (age ATB<20 and age at diagnosis<35) is estimated to be even higher. We assumed that the risk of early-onset breast cancer is high because those who inherited mutated breast cancer-related genes (heterozygotes) from their parent(s) may have lost the function of the wild-allele following radiation exposure. To test this possibility, we screened archived tissues for Japanese-specific founder mutations of breast cancer-related genes (two in the BRCA1 gene, one in the BRCA2 gene and one in the ATM gene) and of a founder mutation in the CHEK2 gene (European population) that has not been surveyed among Japanese, and investigated whether or not there was an accumulation of heterozygotes for these genes. Either PCR-RFLP or PCR-direct sequencing was used for analysis of founder mutations. Formalin-fixed and paraffin-embedded cancer tissues of the breast and ovary were used. Study subjects (about 550 cases) consisted of four groups (with almost the same number for each group): (I) Life span study (LSS) cohort, (II) non-LSS cohort, with ages at diagnosis 45 years old or younger, (III) LSS cohort, and (IV) non-LSS cohort, with ages at diagnosis between 55 and 69 years old. No heterozygote of the founder mutations was detected in the ATM and CHK2 genes. In the BRCA1 or BRCA2 gene, each founder mutation had one or two heterozygotes, and there were four heterozygotes in total (one in Group I, two in Group II, one in Group III, and none in Group IV). The results did not support the possibility that early-onset cases in A-bomb survivors (Group I) are attributable to founder mutations in the breast cancer-related genes (BRCA1, BRCA2, ATM or CHEK2 gene).
