RESUMO
According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C>T, rs2981745, located in the DMBT1 promoter; and DMBT1 c.124A>C, p.Thr42Pro, rs11523871(odds ratio [OR]=1.66, 95% confidence interval [CI]=1.21-2.29, P=0.0017; and OR=1.66; 95% CI=1.21-2.28, P=0.0016, respectively), based on 1,195 BRCA1/2 mutation-negative German breast cancer families and 1,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5'-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk.
Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Receptores de Superfície Celular/genética , Adulto , Idoso , Neoplasias da Mama Masculina/genética , Proteínas de Ligação ao Cálcio , Estudos de Casos e Controles , Proteínas de Ligação a DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Fatores de Risco , Proteínas Supressoras de TumorRESUMO
BACKGROUND: Viral load quantification is established in the clinical management of chronic Hepatitis B virus (HBV) infection for assessing efficacies and resistance developments in anti-viral drug treatment. OBJECTIVES: The fully automated COBAS AmpliPrep/COBAS TaqMan HBV Test, v2.0 was evaluated for the linear measuring range and the inclusivity of HBV genotype determination in EDTA plasma and serum samples. STUDY DESIGN: Two kit lots of the test were used to determine the linear measuring range as well as linearity and limit of detection applying different concentration levels of specimens representing HBV genotypes A to H along with a pre-core mutant and the WHO Standard. RESULTS: The COBAS AmpliPrep/COBAS TaqMan HBV Test, v2.0 displayed a linear measuring range of seven log(10) steps from 20IU/mL (lower limit of quantification) to 2.3E+08IU/mL (upper limit of quantification) yielding similar results for EDTA plasma and serum. Inclusivity was shown by reliable quantification of HBV genotypes A to H at different concentration levels. The >or=95% hit rate LOD was 15IU/mL for genotypes C, D, F, G, the pre-core mutant and the WHO Standard and 20IU/mL for genotypes A, B, E and H matching the test's lower limit of quantification. 95% PROBIT analysis yielded concentrations of 8.9IU/mL for the WHO Standard and of 6.0-16.4IU/mL for the genotypes. CONCLUSIONS: The COBAS AmpliPrep/COBAS TaqMan HBV Test, v2.0 provides genotype inclusivity for accurate viral load monitoring in serum and EDTA plasma samples and supports clinical routine in the management of HBV infection.