Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma

Timothy Best; Dalin Li; Andrew D. Skol; Tomas Kirchhoff; Sarah A. Jackson; Yutaka Yasui; Smita Bhatia; Louise C. Strong; Susan M. Domchek; Katherine L. Nathanson; Olufunmilayo I. Olopade; R. Stephanie Huang; Thomas M. MacK; David V. Conti; Kenneth Offit; Wendy Cozen; Leslie L. Robison; Kenan Onel

doi:10.1038/nm.2407

Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma

Timothy Best, Dalin Li, Andrew D. Skol, Tomas Kirchhoff, Sarah A. Jackson, Yutaka Yasui, Smita Bhatia, Louise C. Strong, Susan M. Domchek, Katherine L. Nathanson, Olufunmilayo I. Olopade, R. Stephanie Huang, Thomas M. MacK, David V. Conti, Kenneth Offit, Wendy Cozen, Leslie L. Robison, Kenan Onel

Experimental and Clinical Pharmacology

Research output: Contribution to journal › Article › peer-review

138 Scopus citations

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.

Original language	English (US)
Pages (from-to)	941-943
Number of pages	3
Journal	Nature Medicine
Volume	17
Issue number	8
DOIs	https://doi.org/10.1038/nm.2407
State	Published - Aug 2011

Bibliographical note

Funding Information:
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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Best, T., Li, D., Skol, A. D., Kirchhoff, T., Jackson, S. A., Yasui, Y., Bhatia, S., Strong, L. C., Domchek, S. M., Nathanson, K. L., Olopade, O. I., Huang, R. S., MacK, T. M., Conti, D. V., Offit, K., Cozen, W., Robison, L. L., & Onel, K. (2011). Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma. Nature Medicine, 17(8), 941-943. https://doi.org/10.1038/nm.2407

Best, T, Li, D, Skol, AD, Kirchhoff, T, Jackson, SA, Yasui, Y, Bhatia, S, Strong, LC, Domchek, SM, Nathanson, KL, Olopade, OI, Huang, RS, MacK, TM, Conti, DV, Offit, K, Cozen, W, Robison, LL & Onel, K 2011, 'Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma', Nature Medicine, vol. 17, no. 8, pp. 941-943. https://doi.org/10.1038/nm.2407

@article{7a353569bcf249da82c594a57be92434,

title = "Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma",

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.",

author = "Timothy Best and Dalin Li and Skol, {Andrew D.} and Tomas Kirchhoff and Jackson, {Sarah A.} and Yutaka Yasui and Smita Bhatia and Strong, {Louise C.} and Domchek, {Susan M.} and Nathanson, {Katherine L.} and Olopade, {Olufunmilayo I.} and Huang, {R. Stephanie} and MacK, {Thomas M.} and Conti, {David V.} and Kenneth Offit and Wendy Cozen and Robison, {Leslie L.} and Kenan Onel",

note = "Funding Information: 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{\textquoteright}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.",

year = "2011",

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doi = "10.1038/nm.2407",

language = "English (US)",

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pages = "941--943",

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T1 - Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma

AU - Best, Timothy

AU - Li, Dalin

AU - Skol, Andrew D.

AU - Kirchhoff, Tomas

AU - Jackson, Sarah A.

AU - Yasui, Yutaka

AU - Bhatia, Smita

AU - Strong, Louise C.

AU - Domchek, Susan M.

AU - Nathanson, Katherine L.

AU - Olopade, Olufunmilayo I.

AU - Huang, R. Stephanie

AU - MacK, Thomas M.

AU - Conti, David V.

AU - Offit, Kenneth

AU - Cozen, Wendy

AU - Robison, Leslie L.

AU - Onel, Kenan

N1 - Funding Information: 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.

PY - 2011/8

Y1 - 2011/8

N2 - 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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Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma

Abstract

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