RESUMO
PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition.
Assuntos
Neoplasias da Mama/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Adulto , Proteína BRCA2/fisiologia , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , LinhagemRESUMO
We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Penetrância , RNA Helicases/genética , Adulto , Códon sem Sentido , Frequência do Gene , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , LinhagemRESUMO
We screened individuals from 443 familial breast cancer pedigrees and 521 controls for ATM sequence variants and identified 12 mutations in affected individuals and two in controls (P = 0.0047). The results demonstrate that ATM mutations that cause ataxia-telangiectasia in biallelic carriers are breast cancer susceptibility alleles in monoallelic carriers, with an estimated relative risk of 2.37 (95% confidence interval (c.i.) = 1.51-3.78, P = 0.0003). There was no evidence that other classes of ATM variant confer a risk of breast cancer.
Assuntos
Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Alelos , Proteínas Mutadas de Ataxia Telangiectasia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , LinhagemRESUMO
The biodegradation of 16 US. EPA-listed polycyclic aromatic hydrocarbons (sigma PAHs), with accompanying humification and microbial community structure changes during simulated in-vessel composting-bioremediation of an aged coal-tar-contaminated soil amended with green waste were studied over 56 days. The experimental design compared one constant temperature profile (TC=38 degrees C) with three variable temperature profiles (TP1, TP2 and TP3), including treatment at 70 degrees C to comply with regulatory requirements. Greatest sigma PAHs removal (75.4+/-0.1%; k(1)=0.026 day(-1), R(2)=0.98) occurred at TC=38 degrees C compared to all variable temperature profiles TP1 (62.1+/-11.0%; k(1)=0.016 day(-1), R(2)=0.93), TP2 (71.8+/-8.2%; k(1)=0.021 day(-1), R(2)=0.95) and TP3 (45.3+/-9.7%; k(1)=0.010 day(-1), R(2)=0.91). This study proved that using thermophilic temperatures (70 degrees C) towards the end of in-vessel composting processes (TP2) resulted in greater sigma PAHs removal than using other variable temperature profiles (TP1, TP3), as long as the increase was stepwise via an intermediate temperature (55 degrees C). Phospholipid fatty acid (PLFA) signatures indicated that use of thermophilic temperatures towards the end of the in-vessel composting-bioremediation (TP2) resulted in a higher fungal to bacterial PLFA ratio and a lower Gram-positive to Gram-negative (G(+)/G(-)) bacterial ratio. Fluorescence excitation-emission matrix (EEM) showed the presence of peaks typical of humic-like (Ex/Em wavelength pair approximately 340/460 nm) and fulvic-acid-like (Ex/Em wavelength pair approximately 245/460 nm) substances, indicating mineralization and/or maturation of the compost. Varying the temperature during in-vessel composting to comply with regulatory requirements for pathogen control, promoted contaminant biodegradation, microbial activity and compost maturation.