Abstract
Survivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy–induced second malignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs in survivors of Hodgkin's lymphoma treated with radiation therapy as children but not as adults. The variants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domain containing 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure. These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology of radiation therapy-induced SMNs.
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Acknowledgements
This work was supported by grants from the US National Institutes of Health (HD0433871, CA129045 and CA40046 to K. Onel, CA55727 to L.L.R., GM089941 and CA139278 to R.S.H., CA58839 to T.M.M. and CA110836 to W.C.); US National Institutes of Health/ National Institute of General Medical Sciences Pharmacogenomics of Anticancer Agents grant U01GM61393 (R.S.H.); contract number N01-PC-35139 (W.C.); the US Army Medical Research and Materiel Command (Department of Defense PR054600 to W.C. and Department of Defense DAMD 17-097-1-7147 to K. Offit); the American Cancer Society–Illinois Division (K. Onel); the American Lebanese Syrian Associated Charities (L.L.R.); the Leukemia Lymphoma Society (TR 6137-07 to W.C. and TR 6202-09 to T.K.); the Breast Cancer Research Foundation (S.M.D., K.L.N. and K. Offit); the Lymphoma Foundation (K. Offit); the Robert and Kate Niehaus Research Fund (K. Offit); the University of Chicago Cancer Center Support Grant (#P30 CA14599) (R.S.H.); the Breast Cancer Specialized Program of Research Excellence Career Development Award (R.S.H.); and the Cancer Research Foundation (K. Onel). We thank the University of Chicago Pharmacogenomics of Anticancer Agents Research Group cell core for providing lymphoblastoid cell lines. The collection of some samples from individuals with Hodgkin's lymphoma used in this publication was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The ideas and opinions expressed herein are those of the authors, and no endorsement by the State of California Department of Health Services is intended or should be inferred. We thank N.A. Ellis for many productive discussions and thoughtful feedback. We are especially grateful for the contributions of the many participating subjects and their parents, without whom this work would not have been possible.
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T.B. and K. Onel designed the study and wrote the manuscript with substantial contributions from A.D.S., Y.Y., S.B., L.C.S., R.S.H., T.M.M., D.V.C., K. Offit, W.C. and L.L.R.; T.B. performed the experiments and undertook the analysis; D.L., A.D.S., T.K., and Y.Y. performed data analysis; S.A.J., S.M.D., K.L.N., O.I.O., W.C. and L.L.R. provided clinical samples and performed analysis of subject data; K. Onel directed the project. All authors contributed to the final manuscript.
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Best, T., Li, D., Skol, A. et al. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma. Nat Med 17, 941–943 (2011). https://doi.org/10.1038/nm.2407
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DOI: https://doi.org/10.1038/nm.2407
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