Study design used to develop a PRS for radiogenic breast cancer. Opstal-van Winden and colleagues used a 2-stage approach to identify SNPs interacting with radiotherapy (RT) for breast cancer (BC) risk (top) and subsequently used these to develop a PRS for radiogenic breast cancer in Hodgkin lymphoma (HL) survivors (bottom). Inclusion and matching criteria (left) were used to maximize the power to identify genetic variants associated with risk of radiogenic breast cancer. A SNP (rs10505506) localized to PVT1 significantly associates with risk of radiogenic breast cancer in Hodgkin lymphoma survivors (boxed in red). The PVT1 long noncoding RNA negatively regulates MYC-driven oncogenic transcriptional activity by inhibiting protein degradation. The PVT1 promoter also negatively regulates MYC transcription directly (green). MYC expression drives transcription of downstream target genes via binding to E-box elements in promoters, promoting tumor cell proliferation and survival. c-MYC and PVT1 are coamplified in primary breast cells exposed to ionizing radiation (purple bar shows approximate location of amplicon identified by Wade and colleagues⁶ ). A risk allele for radiogenic cancer in Hodgkin lymphoma survivors was identified in the PRDM1 gene.⁵  PRDM1 is a negative regulator of c-MYC transcription, but PRDM1 upregulation in response to ionizing radiation is attenuated in cells carrying the risk variant, leading to elevated c-MYC expression and acquisition of a pro-proliferative phenotype. Additional work is required to determine functionality of the rs10505506 variant, although it is plausible this also operates via the MYC pathway. Approximate amplicon, gene, and SNP locations are based on GRCh37.