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; Flora E van Leeuwen

doi:10.1182/blood-2018-07-862607

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 CouchPaul Pharoah, Nick Orr, Douglas F Easton, Berthe M P Aleman, Louise C Strong, Smita Bhatia, Rosie Cooke, Leslie L Robison, Anthony J Swerdlow, Flora E van Leeuwen

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 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.

Original language	English
Journal	Blood
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2018-07-862607
Publication status	Published - 2019

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Opstal-van Winden, A. W. J., de Haan, H. G., Hauptmann, M., Schmidt, M. K., Broeks, A., Russell, N. S., Janus, C. P. M., Krol, A. D. G., van der Baan, F. H., De Bruin, M. L., van Eggermond, A. M., Dennis, J., Anton Culver, H., Haiman, C. A., Sawyer, E. J., Cox, A., Devilee, P., Hooning, M. J., Peto, J., ... van Leeuwen, F. E. (2019). Genetic susceptibility to radiation-induced breast cancer after Hodgkin Lymphoma. Blood. https://doi.org/10.1182/blood-2018-07-862607

Opstal-van Winden, AWJ, de Haan, HG, Hauptmann, M, Schmidt, MK, Broeks, A, Russell, NS, Janus, CPM, Krol, ADG, van der Baan, FH, De Bruin, ML, van Eggermond, AM, Dennis, J, Anton Culver, H, Haiman, CA, Sawyer, EJ, Cox, A, Devilee, P, Hooning, MJ, Peto, J, Couch, FJ, Pharoah, P, Orr, N, Easton, DF, Aleman, BMP, Strong, LC, Bhatia, S, Cooke, R, Robison, LL, Swerdlow, AJ & van Leeuwen, FE 2019, 'Genetic susceptibility to radiation-induced breast cancer after Hodgkin Lymphoma', Blood. https://doi.org/10.1182/blood-2018-07-862607

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title = "Genetic susceptibility to radiation-induced breast cancer after Hodgkin Lymphoma",

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 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.",

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

note = "Copyright {\textcopyright} 2018 American Society of Hematology.",

year = "2019",

doi = "10.1182/blood-2018-07-862607",

language = "English",

journal = "Blood",

issn = "0006-4971",

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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

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 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.

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 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.

U2 - 10.1182/blood-2018-07-862607

DO - 10.1182/blood-2018-07-862607

M3 - Journal article

C2 - 30573632

SN - 0006-4971

JO - Blood

JF - Blood

ER -

Genetic susceptibility to radiation-induced breast cancer after Hodgkin Lymphoma

Abstract

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