Background: In Hodgkin’s lymphoma (HL) radiation therapy including the mediastinum is known to cause long time cardiac side effects.
Method: A cohort of 183 previous HL patients who received radiotherapy involving the mediastinum during the period of 1965-1995 were dichotomized into patients with or without known cardiac complications. This was done after a separate study visit performed with a range of 13-43 years from diagnosis (median 23 years). A complication was defined as having a medical record of any of the following clinical conditions: angina, myocardial infarction, congestive heart failure or valvular disease. DNA was extracted from whole blood and analyzed using Infinum OncoArray-500K. We analyzed a set of 4341 single nucleotide polymorphisms (SNPs) representing 167 genes previously associated with late side effects of radiotherapy or associated with the normal myocyte function, ischemic heart disease, primary restrictive cardiomyopathy or valvular disease. The association between cardiac status and alterations in SNPs was examined. Forty-six of the patients had also received doxorubicin, an anthracycline associated with late cardiotoxic side effects.
Results: A SNP of SETD7 (intron), rs2725790, significantly differed between the two groups (allelic test, p = 9.2E-6, maxT permutation test p=0.024, logistic regression p=0.00013). To take prior anthracycline therapy into account, logistic regression was performed adjusting for anthracycline therapy (logistic regression p = 0.00020).
Conclusion: This study indicates that constitutional differences in SETD7, a gene associated with epigenetic regulation of cardiomyogenesis and response to cardiac hypoxia may be involved in the risk of developing late cardiac side effect after radiation therapy of the mediastinum in the treatment of HL.
Johan Linderoth, Eva Freyhult, Ellinor Andreasson, Ann-sofie Johansson, Anne Andersson, Ingrid Glimelius, Gunilla Enblad, Daniel Molin