Pharmacogenomics of anthracycline-induced cardiotoxicity in children with cancer

Anthracyclines, such as doxorubicin, are commonly being used to treat adult and
childhood leukemia and various solid tumors, and are highly effective. Up to
60% of all childhood cancer patients receive anthracyclines. Even though some
patients can tolerate high doses of anthracyclines, up to 16% of patients
treated will suffer severe cardiotoxicity, some even at low doses, and will
develop restrictive or dilated cardiomyopathy, eventually leading to death or
requirement of heart transplantation or life-long treatment for chronic cardiac
failure, and 33-41% will be moderately affected.3 These devastating effects can
occur immediately after drug use, but also many years after chemotherapy
completion. Genetic factors are most likely to be a major contributor to this
adverse drug reactions.

Objective
The overall goal of this project is to identify the specific genomic markers
associated with severe anthracycline-induced cardiotoxicity to be able to
identify high-risk patients.

The specific objective of this proposal
To validate and replicate gene variants associated with increased risk of
anthracycline-induced cardiotoxicity that have been found in the GATC study in
survivors of cancer who have been treated in the Emma Children*s Hospital/
Academic Medical Center (EKZ/AMC).

Case control study
A saliva sample will be obtained and patient DNA will be extracted. DNA will be
genotyped using a high-throughput genotyping assay.Genes with SNPs found to be
highly linked with the ADR might be further investigated by sequencing samples
for SNPs not genotyped initially, including SNPs and mutations in promoter
regions, splice sites, and other regulatory sites.

Only a saliva sample will be obtained. If there are unexpected problems with
the analyses a blood sample will be obtained. So the risks are minimal.
Furthermore the analyses will be performed anonymous.