Although genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with cancer, the contribution to risk of these variants is small, rendering them of little use clinically. Whereas GWAS focus on main effects, complex diseases are also influenced by many environmental factors that may affect the association between SNPs and disease. We hypothesized that a variant identified by GWAS to have a small effect in the general population may actually exert a large effect in a subset of individuals sharing a common environmental context. To test this, we performed GWAS of two therapy-induced cancers: radiation therapy-induced second cancers after Hodgkin lymphoma, and therapy-related acute myeloid leukemia. We found that common variants can have large effects in the context of specific etiological exposures. Thus, genomic studies incorporating exposures may reveal patient subsets for whom specific SNPs contribute meaningfully to disease. In the future, a major challenge will be to design genetic studies taking advantage of exposures shared by cases and controls when the contribution to disease of the exposure is less obvious than for therapy-induced cancers. Learning objectives: 1. To understand the implications of cancer as a complex disease for studies investigating genetic susceptibilities to cancer. 2. To understand the strengths and limitations of genome-wide association studies (GWAS). 3. To understand the role of PRDM1 in defending against radiation-induced second cancers.