Association between CASP7 and CASP14 genetic polymorphisms and the risk of childhood leukemia

Abstract

Leukemia is the most common childhood cancer, which is the major cause of morbidity and mortality among pediatric cancers in Korea as well as worldwide. Genetic variation related to apoptosis and cell cycle system may increase the risk of childhood leukemia. To identify susceptible genetic biomarkers of apoptosis and cell cycle mechanisms for childhood leukemia, a hospital based case-control study has been performed including 136 childhood leukemia cases and 254 controls matched on sex and 5-year interval age. After quality control of biospecimen, a total of 63 patients and 148 controls were included in this study. 304 SNPs in 31 gene regions were selected according to CGEMS, CGAP, SNP500 database and the International HapMap Project. Genotyping was performed using an Illumina GoldenGate oligonucleotide pool assay (OPA) panel. Genetic factors associated with childhood leukemia were assessed by both an additive model and dominant model using unconditional logistic regression models adjusting for age and birth weight. The minimum P-value (minP) test and the false discovery rate (FDR) test were used to evaluate statistically significant association at gene level and to minimize the false positive rate. Both SNP and gene-based analyses presented associations with the risk of childhood leukemia for 5 genes: CASP7, CASP14, CASP8AP2, MYC, and RIPK1 (Ptrend < 0.05 in additive models). Furthermore, in the gene level test two genes represented statistically significant associations: CASP7 (rs12416109 and rs3814231, Ptrend = 0.002 and 0.009, respectively, minP = 0.013, FDR = 0.042) and CASP14 (rs8110862, Ptrend < 0.001, minP = 0.002, FDR = 0.027). In dominant model CASP7 rs12416109 represented increase risk of childhood leukemia (AG+GG vs AA

OR=4.30, 95% CI 1.70-10.87). On the other hand, CASP7 rs3814231 and CASP14 rs8110862 represented decrease risk of childhood leukemia (CT+TT vs CC

OR=0.46, 95% CI 0.24-0.87 and AC+CC vs AA

OR=0.34, 95% CI 0.18-0.63, respectively). When stratified by subtype groups (ALL and AML), CASP14 was still statistically significant in each subtype. This study suggests that genetic polymorphisms in apoptosis and cell cycle related genes might play a role in childhood leukemia development.