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. 2019 Mar 7;133(10):1130-1139.
doi: 10.1182/blood-2018-07-862607. Epub 2018 Dec 20.

Genetic susceptibility to radiation-induced breast cancer after Hodgkin lymphoma

Annemieke W J Opstal-van Winden  1 , Hugoline G de Haan  1 , Michael Hauptmann  1 , Marjanka K Schmidt  1   2 , Annegien Broeks  3 , Nicola S Russell  4 , Cécile P M Janus  5 , Augustinus D G Krol  6 , Frederieke H van der Baan  1 , Marie L De Bruin  1   7 , Anna M van Eggermond  1 , Joe Dennis  8 , Hoda Anton-Culver  9 , Christopher A Haiman  10 , Elinor J Sawyer  11 , Angela Cox  12 , Peter Devilee  13   14 , Maartje J Hooning  15 , Julian Peto  16 , Fergus J Couch  17 , Paul Pharoah  18   19 , Nick Orr  20 , Douglas F Easton  8   18 , Berthe M P Aleman  4 , Louise C Strong  21 , Smita Bhatia  22 , Rosie Cooke  23 , Leslie L Robison  24 , Anthony J Swerdlow  23   25 , Flora E van Leeuwen  1
Affiliations

Genetic susceptibility to radiation-induced breast cancer after Hodgkin lymphoma

Annemieke W J Opstal-van Winden et al. Blood. .

Abstract

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 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 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 fourfold 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.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Study design. (A) First step: case-only study. (B) Second step: case-control study. IOR, interaction odds ratio. *See Mavaddat et al.
Figure 2.
Figure 2.
Risk of breast cancer after chest RT by tertiles of the RT-interaction-PRS among HL survivors.
Figure 3.
Figure 3.
Risk of breast cancer after chest RT by deciles of the BC-PRS in the breast cancer after HL case-control analysis.
See this image and copyright information in PMC

Comment in

References

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