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Blood. 2018 Dec 20. pii: blood-2018-07-862607. doi: 10.1182/blood-2018-07-862607. [Epub ahead of print]

Genetic susceptibility to radiation-induced breast cancer after Hodgkin Lymphoma.

Author information

1
Department of Epidemiology and Biostatistics, The Netherlands Cancer Institute, Amsterdam, Netherlands.
2
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
3
Division of Molecular Pathology, Core Facility Molecular Pathology & Biobanking, The Netherlands Cancer Institute, Amsterdam, Netherlands.
4
Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
5
Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
6
Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.
7
Copenhagen Centre for Regulatory Science (CORS), University of Copenhagen, Copenhagen, Denmark.
8
Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
9
Department of Epidemiology, University of California Irvine, Irvine, United States.
10
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
11
Innovation Hub, Guy’s Cancer Centre, King's College London, London, United Kingdom.
12
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, United Kingdom.
13
Department of Pathology, Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
14
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
15
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
16
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.
17
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
18
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.
19
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
20
Genetics, MD Anderson Cancer Center, Houston, TX, United States.
21
Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL, United States.
22
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
23
Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, United States.
24
Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
25
Department of Epidemiology and Biostatistics, The Netherlands Cancer Institute, Amsterdam, Netherlands; f.v.leeuwen@nki.nl.

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.

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