Genetic susceptibility to radiation-induced breast cancer after Hodgkin Lymphoma

Annemieke W.J. Opstal-van Winden, Hugoline G. de Haan, Michael Hauptmann, Marjanka K. Schmidt, Annegien Broeks, Nicola S. Russell, Cécile P.M. Janus, Augustinus D.G. Krol, Frederieke H. van der Baan, Marie L. De Bruin, Anna M. van Eggermond, Joe Dennis, Hoda Anton Culver, Christopher A. Haiman, Elinor J. Sawyer, Angela Cox, Peter Devilee, Maartje J. Hooning, Julian Peto, Fergus J. Couch, Paul Pharoah, Nick Orr, Douglas F. Easton, Berthe M.P. Aleman, Louise C. Strong, Smita Bhatia, Rosie Cooke, Leslie L. Robison, Anthony J. Swerdlow and Flora E. van Leeuwen

Key points

  • The risk of RT-induced breast cancer after Hodgkin lymphoma is strongly associated with a PRS for breast cancer in the general population.

  • A PRS, based on nine SNPs interacting with RT in the occurrence of breast cancer after HL, also increased RT-induced breast cancer risk.


Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211,155 germline single nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4,671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate <20%), of which one SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a 4-fold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients.

  • Submitted July 9, 2018.
  • Accepted December 12, 2018.