Genetic variability of homologous recombination repair genes and radiotherapy cardiotoxicity
PO-1362
Abstract
Genetic variability of homologous recombination repair genes and radiotherapy cardiotoxicity
Authors: Tanja Marinko1, Franja Dugar2, Vita Dolžan3, Katja Goričar4
1Institute of Oncology Ljubljana, Radiotherapy department, University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia; 2University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia; 3University of Ljubljana, Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, Pharmacogenetics Laboratory, Ljubljana, Slovenia; 4Faculty of Medicine, University of Ljubljana, Institute of Biochemistry and Molecular Genetics, Pharmacogenetics Laboratory, Ljubljana, Slovenia
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Purpose or Objective
Despite the significant impact of adjuvant radiotherapy (RT) on the
survival of HER2-positive early breast cancer patients, they may also
experience treatment-related adverse events. The homologous recombination repair
(HRR) pathway is involved in the repair of double-strand breaks, the most
cytotoxic DNA lesions caused by radiation. Genetic variability of DNA repair genes
could contribute to the interindividual variability in the occurrence of
adverse events. Therefore, the study aimed to evaluate the association
of polymorphisms in HRR genes on the occurrence of RT cardiotoxicity in breast
cancer patients.
Material and Methods
Our study included 101 HER2-positive early breast
cancer patients treated with adjuvant radiotherapy. Markers of cardiotoxicity investigated
in the study were LVEF reduction, serum NT-proBNP concentration, and NYHA
grade. DNA was isolated from buccal swab samples. All patients were genotyped
for eight single nucleotide polymorphisms (NBN
rs1805794, rs709816, and rs1063054, RAD51
rs1801320, rs1801321, and rs12593359, XRCC3
rs1799794 and rs861539) using competitive allele-specific PCR. Logistic
regression was used to evaluate the association with cardiotoxicity.
Results
Median time after
adjuvant RT was 4.0 (2.6-5.4) years. LVEF reduction was observed in 9 (8.9%)
patients, increased NT-proBNP in 36 (25.6%) patients, while 17 (16.8%) patients
had NYHA grade 2. Among clinical parameters, hyperlipidemia and higher ITM were
associated with increased risk for NYHA grade 2 (P=0.012 and P=0.006,
respectively). Carriers of two polymorphic RAD51
rs1801321 alleles were significantly more likely to have higher NYHA grade in
the univariable analysis (OR=10.0; 95 % CI=1.63-61.33; p=0.013) and after
adjustment for clinical variables (OR=9.27; 95 % CI=1.28-67.02; p=0.027).
Carriers of two polymorphic RAD51
rs12593359 were significantly less likely to have higher NYHA grade in
univariable analysis (OR=0.09; 95 % CI=0.01-0.79; p=0.030) and after adjustment
for clinical variables (OR=0.07; 95 % CI=0.01-0.81; p=0.034). None of the
investigated polymorphisms was associated with LVEF reduction or serum
NT-proBNP concentration.
Conclusion
HRR gene RAD51
polymorphisms might contribute to RT cardiotoxicity and could be used
as biomarkers in tailoring breast cancer patient treatment.
Research grants: ARRS J3-1753, ARRS J3-2527, P1-0170 and P3-0321.