RESUMO
Apoptosis is an essential physiological process that regulates cellular proliferation. Here, we explored the effect of DNA sequence variation within the BCL-2 gene on prostate cancer susceptibility in three clinical populations, consisting of 428 African Americans, 214 Jamaicans and 218 European Americans. We observed a 70% reduced risk for prostate cancer among the European Americans who had possessed two copies of a promoter variant -938C/A. Additionally, common BCL-2 haplotypes appeared to influence prostate cancer risk; however, studies in larger data sets are needed to confirm our findings. Our data suggest that inherited BCL-2 variants may be associated with a decrease in prostate cancer susceptibility.
Assuntos
Carcinoma/genética , Predisposição Genética para Doença , Variação Genética , Mutação em Linhagem Germinativa , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Adulto , Negro ou Afro-Americano/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Frequência do Gene , Genótipo , Haplótipos , Humanos , Padrões de Herança , Jamaica/etnologia , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fases de Leitura Aberta , Elementos Reguladores de Transcrição , População Branca/genéticaRESUMO
Prostate cancer is a common malignancy that disproportionately affects African-American men. Environmental factors and variation in genes responsible for chemical and dietary carcinogen metabolism and DNA damage repair may modulate risk. Fourteen single nucleotide polymorphisms in NAT2 and four NER genes (ERCC1, XPF/ERCC4, XPG/ERCC5 and CSB/ERCC6) were genotyped in a case-control study of 254 African-American prostate cancer cases and 301 healthy controls from Washington, DC. Smoking status, BMI, age and genetic ancestry were included as covariates in the association analyses. We found that individuals homozygous for the XPG/ERCC5 -72C/T promoter polymorphism had a significant reduction in risk, for prostate cancer (OR=0.12; 95% CI=0.03-0.48). A haplotype trend regression test also revealed a protective effect for the haplotype bearing the T allele (P=0.003). In silica analyses suggest a functional implication for the promoter variant since it deletes a GCF transcriptional factor-binding site responsible for the downregulation of transcription. The protective effect of the promoter SNP on risk for prostate cancer was independent of smoking. In contrast, none of the SNPs typed for NAT2, ERCC1, ERCC4 and ERCC6 showed significant association with risk. Additional tests for genotype interactions were not significant. We note that there may be other factors, such as dietary exposures, which may modulate prostate cancer risk in combination with genetic variation within the NAT2 and NER genes. Our results, in combination with previous observations of LOH for ERCC5 in prostate tumors, provide further evidence for a role of XPG/ERCC5 in the etiology of prostate cancer.