Impact of HFE mutations on cardiac status in survivors of childhood high-risk ALL: Dana-Farber Cancer Institute Childhood ALL 05-159.

Abstract

9508 Background: Doxorubicin (DOX) chemotherapy has been associated with progressive cardiac dysfunction. Laboratory studies suggest DOX-induced cardiac damage may be due to the formation of DOX-iron complexes, leading to free radical formation. Individuals with hereditary hemochromatosis (HH), a genetic disorder that causes increased iron levels, may be at greater risk for developing DOX-associated cardiotoxicity. Methods: The Dana-Farber Cancer Institute Childhood Acute Lymphoblastic Leukemia (ALL) Consortium collected peripheral blood from 185 long-term survivors of high-risk ALL to assess the 2 most frequent allelic variants of the HFE gene associated with HH: C282Y and H63D. Genomic DNA was sequenced using a clinically validated kit from Biotage Inc (PyroMark HFE Cat#40-0053) run on a Pyrosequencer instrument (PSQ HS 96, Biotage Inc) and by taqman and sequenom SNP assay. Echocardiography assessed left ventricular (LV) structure and function. Serum cardiac troponin-T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) assayed during therapy reflect myocardial injury and cardiomyopathy, respectively. Z scores were derived by comparison to a normal healthy population. Results: 21% (39/185) of patients were heterozygous for H63D; 2 were homozygous. 9% (17/185) of patients were heterozygous for C282Y; 1 was homozygous. HFE mutations were not significantly associated with elevations in cTnT or NT-proBNP. At 2 years post randomization, mean LV fractional shortening, LV mass, and LV end diastolic posterior wall thickness z scores were significantly worse than normal for children who were heterozygous (-0.62, SD 1.35, p=0.03; -0.71, SD 0.85, p<0.001; -0.65, SD 1.53, p=0.04, respectively), but not for those who were wild type, except for LV mass (-0.50, SD 1.2, p=0.003). Homozygotes were not included in the analysis due to small numbers. Conclusions: The frequency of HFE mutations in these patients is similar to the general population. HFE heterozygotes showed significantly lower LV function, mass and wall thickness compared to a normal population. These results support the need for future research on the role of these mutations in DOX-induced cardiotoxicity.