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. 2011 Jul 24;17(8):941-3.
doi: 10.1038/nm.2407.

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

Timothy Best  1 , 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
Affiliations

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

Timothy Best et al. Nat Med. .

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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Figures

Figure 1
Figure 1. Variants at 6q21 are associated with both RT-induced SMNs and PRDM1 levels before and after radiation exposure
(a) Shown is the regional association plot of the 6q21 locus. The −log (P value) for SNPs in this region are shown with respect to genomic position. Genotyped SNPs are in red; imputed SNPs are in black. The line at −log (P) = 7 denotes the threshold for genome-wide significance. Recombination rates (taken from HapMap) and genes within this region are also shown (top panel). LD structure based on D’ values for the GWAS data are shown (bottom panel). NCBI build 36 was used for all map locations. (b) Shown is the western blot analysis over time for PRDM1 in eight lymphoblastoid cell lines, four homozygous for the chromosome 6q21 protective haplotype and four homozygous for the risk haplotype, treated with 10 Gy gamma irradiation. The protective haplotype was associated with both higher baseline PRDM1 protein levels than the risk haplotype and a marked induction of PRDM1 following irradiation. In contrast, PRDM1 was not induced by irradiation in cells homozygous for the risk haplotype.
Figure 1
Figure 1. Variants at 6q21 are associated with both RT-induced SMNs and PRDM1 levels before and after radiation exposure
(a) Shown is the regional association plot of the 6q21 locus. The −log (P value) for SNPs in this region are shown with respect to genomic position. Genotyped SNPs are in red; imputed SNPs are in black. The line at −log (P) = 7 denotes the threshold for genome-wide significance. Recombination rates (taken from HapMap) and genes within this region are also shown (top panel). LD structure based on D’ values for the GWAS data are shown (bottom panel). NCBI build 36 was used for all map locations. (b) Shown is the western blot analysis over time for PRDM1 in eight lymphoblastoid cell lines, four homozygous for the chromosome 6q21 protective haplotype and four homozygous for the risk haplotype, treated with 10 Gy gamma irradiation. The protective haplotype was associated with both higher baseline PRDM1 protein levels than the risk haplotype and a marked induction of PRDM1 following irradiation. In contrast, PRDM1 was not induced by irradiation in cells homozygous for the risk haplotype.
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References

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