TY - JOUR
T1 - Genetic susceptibility to radiation-induced breast cancer after Hodgkin lymphoma
AU - Opstal-Van Winden, Annemieke W.J.
AU - De Haan, Hugoline G.
AU - Hauptmann, Michael
AU - Schmidt, Marjanka K.
AU - Broeks, Annegien
AU - Russell, Nicola S.
AU - Janus, Cécile P.M.
AU - Krol, Augustinus D.G.
AU - Van Der Baan, Frederieke H.
AU - De Bruin, Marie L.
AU - Van Eggermond, Anna M.
AU - Dennis, Joe
AU - Anton-Culver, Hoda
AU - Haiman, Christopher A.
AU - Sawyer, Elinor J.
AU - Cox, Angela
AU - Devilee, Peter
AU - Hooning, Maartje J.
AU - Peto, Julian
AU - Couch, Fergus J.
AU - Pharoah, Paul
AU - Orr, Nick
AU - Easton, Douglas F.
AU - Aleman, Berthe M.P.
AU - Strong, Louise C.
AU - Bhatia, Smita
AU - Cooke, Rosie
AU - Robison, Leslie L.
AU - Swerdlow, Anthony J.
AU - Van Leeuwen, Flora E.
N1 - Funding Information:
This work was supported by Dutch Cancer Society grant 2010-4720 (F.E.v.L.). The UK Hodgkin Lymphoma cohort was supported by Breast Cancer Now and the European Commission. The Institute of Cancer Research acknowledges funding from the National Institute for Health Research to the Biomedical Research Centre. The Childhood Cancer Survivor study was supported by the National Institutes of Health, National Cancer Institute (CA55727 [principal investigator: G. T. Armstrong]). Support to St. Jude Children’s Research Hospital was also provided by the Cancer Center Support (CORE) grant (CA21765 [principal investigator: C. Roberts]) and the American Lebanese-Syrian Associated Charities (ALSAC).
Funding Information:
For the Dutch Hodgkin Lymphoma cohort, the authors thank Ph. M. P. Poortmans from Elisabeth Hospital Tilburg at the time of the study, M. L. M. Lybeert from Catherina Hospital Eindhoven, G. W. Imhoff from Groningen University Medical Center, J. M. M. Raemaekers from Rijnstate Hospital/Radboud University Medical Center Nijmegen at the time of the study, J. M. Zijlstra from VU Medical Center Amsterdam, and J. H. Borger fromMaastricht University Medical Center for inclusion of HL patients. The UK Hodgkin Lymphoma cohort thanks the study participants, study staff, and clinicians who participated in the study as listed in the authorship and acknowledgments in Cooke et al.32 This work was supported by Dutch Cancer Society grant 2010-4720 (F.E.v.L.). The UK Hodgkin Lymphoma cohort was supported by Breast Cancer Now and the European Commission. The Institute of Cancer Research acknowledges funding from the National Institute for Health Research to the Biomedical Research Centre. The Childhood Cancer Survivor study was supported by the National Institutes of Health, National Cancer Institute (CA55727 [principal investigator: G. T. Armstrong]). Support to St. Jude Children's Research Hospital was also provided by the Cancer Center Support (CORE) grant (CA21765 [principal investigator: C. Roberts]) and the American Lebanese-Syrian Associated Charities (ALSAC).
Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019
Y1 - 2019
N2 - 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 generadiation 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 (RTinteraction- 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 chestirradiated 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.
AB - 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 generadiation 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 (RTinteraction- 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 chestirradiated 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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U2 - 10.1182/blood-2018-07-862607
DO - 10.1182/blood-2018-07-862607
M3 - Article
C2 - 30573632
AN - SCOPUS:85062600362
SN - 0006-4971
VL - 133
SP - 1130
EP - 1139
JO - Blood
JF - Blood
IS - 10
ER -