Survivors of bone cancers or soft-tissue sarcomas comprise 17% of the CCSS cohort and 21% of all survivors who experienced SMNs, 20% of which were breast cancer. Risk of cancer was increased among siblings of sarcoma survivors and those of survivors with SMNs. Risk of breast cancer was increased among sarcoma survivors not treated with radiotherapy, and risk of secondary sarcoma was increased in primary sarcoma survivors and those with a family history of cancer.This is consistent with data showing an association between soft tissue sarcoma and breast cancer or sarcomas as SMNs in patients or close relatives and suggests the need for further study of the interactions between genetic predisposition, disease, and treatment. The collection of genomic DNA from the CCSS cohort has provided an opportunity to investigate genetic susceptibility to subsequent cancers. Of particular interest is the demonstration of a strong association between exposure to radiation therapy and the high risk of SNs. Molecular epidemiology studies will be necessary to address the role of genetics in the observed interindividual variation in risk of subsequent cancers and will be possible only with continuing follow-up of this cohort..