RESUMO
Centrosome amplification has been detected in premalignant lesions and in situ tumors in the breast and in over 70% of invasive breast tumors, and has been associated with aneuploidy and tumor development. Based on these observations, the contribution of commonly inherited genetic variation in candidate genes related to centrosome structure and function to breast cancer risk was evaluated in an association study. Seven-hundred and 82 single nucleotide polymorphisms (SNPs) from 101 centrosomal genes were analyzed in 798 breast cancer cases and 843 controls from the Mayo Clinic Breast Cancer Study to assess the association between these SNPs (both individually and combined) and risk of breast cancer in this population. Eleven SNPs out of 782 from six genes displayed associations with breast cancer risk (P < 0.01). Haplotypes in five genes also displayed significant associations with risk. A two SNP combination of rs10145182 in NIN and rs2134808 in the TUBG1 locus (P-interaction = 0.00001), suggested SNPs in mediators of microtubule nucleation from the centrosome contribute to breast cancer. Evaluation of the simultaneous significance of all SNPs in the centrosome pathway suggested that the centrosome pathway is highly enriched (P = 4.76 × 10(-50)) for SNPs that are associated with breast cancer risk. Collections of weakly associated genetic variants in the centrosome pathway, rather than individual highly significantly associated SNPs, may account for a putative role for the centrosome pathway in predisposition to breast cancer.
Assuntos
Neoplasias da Mama/genética , Centrossomo/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Minnesota , Razão de Chances , Medição de Risco , Fatores de RiscoRESUMO
The down-regulation of genes involved in normal cell division can cause aberrant mitoses and increased cell death. Surviving cells exhibit aneuploidy and/or polyploidy. Since mitotic disruption has been linked with tumor development and progression, alterations in the expression or activity of these mitotic regulators may contribute to breast tumor formation. We evaluated associations between common inherited variation in these genes and breast cancer risk. Two hundred and five tagging and candidate functional single nucleotide polymorphisms in 30 genes required for normal cell division were genotyped in 798 breast cancer cases and 843 controls from the Mayo Clinic breast cancer study. Two variants in EIF3A (rs10787899 and rs3824830; P < 0.01) and four variants in SART1 (rs660118, rs679581, rs754532, and rs735942; P(trend) < or = 0.02) were significantly associated with an altered risk of breast cancer along with single variants in RRM2, PSCD3, C11orf51, CDC16, SNW1, MFAP1, and CDC2 (P < 0.05). Variation in both SART1 (P = 0.009) and EIF3A (P = 0.02) was also significant at the gene level. Analyses suggested that SART1 SNPs rs660118 and rs679581 accounted for the majority of the association of that gene with breast cancer. The observed associations between breast cancer risk and genetic variation in the SART1 and EIF3A genes that are required for maintenance of normal mitosis suggest a direct role for these genes in the development of breast cancer.
Assuntos
Antígenos de Neoplasias/genética , Neoplasias da Mama/genética , Fator de Iniciação 3 em Eucariotos/genética , Regulação Neoplásica da Expressão Gênica , Mitose/genética , Polimorfismo de Nucleotídeo Único , Ribonucleoproteínas Nucleares Pequenas/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Meio-Oeste dos Estados Unidos/epidemiologia , Invasividade Neoplásica , Razão de Chances , Linhagem , Fenótipo , Medição de Risco , Fatores de RiscoRESUMO
There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.
