Abstract

Genotype studies were performed to explore the possibility that the risk of PCa is affected by susceptibility alleles in two DNA repair-associated genes, CHK2 checkpoint homolog (S. pombe), (CHEK2) and nibrin (NBN). We also carried out cell irradiation studies on lymphocytes and analyzed them for DNA damage, as determined by the presence of chromosomal aberrations. Results were compared between PCa patients and men with no diagnosis of PCa. Since it is well documented that PCa incidence differs among different races and ethnic groups, we stratified our analysis based on ethnicity.

Lymphoblastoid cells were irradiated with 0.5 Gy of gamma radiation and cytogenetically analyzed for G2 chromosomal breaks and gaps. The number of chromosomal aberrations induced in cells from individuals with and without PCa was not significantly different.

To explore the role of CHEK2 and NBN in prostate cancer risk, their coding regions were sequenced in 20 non-Hispanic and 20 Hispanic PCa patients. In NBN, three novel and 11 previously reported SNPs were identified. No variants were identified in CHEK2 with sequencing.

High throughput genotyping of CHEK2 and NBN SNPs was performed on non-Hispanic Caucasian and Hispanic Caucasian men. For NBN, one mutation identifying a 5bp deletion and six for SNP analysis were analyzed. No deletions were identified. Two NBN SNPs in the Hispanic Caucasian population were associated with an increased risk for PCa. No NBN SNPs were found to be associated with PCa risk in the non-Hispanic Caucasian population. Five intronic CHEK2 SNPs were analyzed. Two SNPs, identified in the non-Hispanic Caucasian population, were associated with increased PCa risk. In the Hispanic Caucasian population, one SNP was associated with a decreased PCa risk when the minor allele was homozygous. Both ethnic groups had significant CHEK2 haplotypes.

To date, there have been no published studies evaluating the role of CHEK2 and NBN in Hispanic Caucasians. The findings have identified genetic polymorphisms in NBN and CHEK2 that are associated with PCa risk in non-Hispanic and Hispanic Caucasian men, supporting the hypothesis that NBN and CHEK2 are associated with PCa risk.