Editors' ChoiceGenomics

Cancer Returns

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Science Translational Medicine  03 Aug 2011:
Vol. 3, Issue 94, pp. 94ec121
DOI: 10.1126/scitranslmed.3002963

In the movie business, a sequel furthers the storyline of the original film. But whether or not there will be a sequel usually is unknown at the time when the initial film is first produced. Similarly, researchers and physicians are unable to predict second malignancies that occur as late sequels of successful treatment of Hodgkin’s lymphoma (HL), and these repeat performances are the second leading cause of mortality in HL survivors. To better understand the genetic variations that increase the likelihood of radiation therapy–induced second malignancies, Best and colleagues performed a genome-wide association study in HL survivors.

Thanks to combination chemo and radiation therapy, HL is a highly curable cancer the first time around. But, approximately 15 to 20% of patients by 30 years after initial diagnosis and treatment suffer second cancers that occur mainly in the mediastinal radiation therapy area and are associated with cumulative radiation dose.

The researchers compared single-nucleotide polymorphisms (SNPs) between two groups of pediatric patients with HL who had been treated with radiation and either did or did not develop second malignancies after a mean latency of 20 years. Two SNPs (rs4946728 and rs1040411) that mapped to chromosome 6q21, between ATG5 (which encodes an autophagy protein) and PRDM1 (the PR domain zinc finger protein 1 gene), achieved genome-wide significant differences between the two groups, even after adjusting for other risk variables. These two SNPs form three common haplotypes in individuals of European descent that represent almost 100% of the haplotypes at this locus.

The investigators defined the second-malignancy risk haplotype to be composed of the risk alleles for both rs4946728 and rs1040411 and demonstrated that an increase in dosage of the risk haplotype was significantly associated with lower expression of PRDM1 mRNA. PRDM1 is a tumor suppressor and encodes a transcriptional repressor that regulates a variety of cellular processes, such as proliferation, differentiation, and apoptosis. In cells that were not treated with radiation, PRDM1 protein was more abundant in cells homozygous for the protective haplotype than in cells homozygous for the risk haplotype and was significantly induced in cells homozygous for the protective haplotype shortly after ionizing radiation exposure. Lastly, Best et al. did not observe a similar association in adults, suggesting that age of radiation exposure might alter the association between the SNPs and second malignancies.

These results are based on a small number of individuals, and the long-range effects of these variants on the expression of other genes or tissue-specific differences in PRDM1 function are unknown. However, these early observations suggest that (i) PRDM1 is a radiation-responsive tumor suppressor and (ii) variants at 6q21 are strongly associated with second malignancies risk after radiation therapy for Hodgkin’s lymphoma in childhood. These findings may help scientists gain an understanding of the etiology of second malignancies in cancer patients treated with radiation and assist in stratifying treatment decisions based on personalized SNP signatures. As should happen more in the movie business, such new information might thwart malignant sequels. Hollywood might take a cue from cancer research.

T. Best et al., Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin’s lymphoma. Nat. Med. 24 July 2011 (10.1038/nm.2407). [Abstract]

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