Exploring the link between MORF4L1 and risk of breast cancer.

INTRODUCTION: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. METHODS: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. RESULTS: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. CONCLUSIONS: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Determinantes sociales de la salud y discapacidad: caso Santiago de Cali / Social determinants of health and disability: the Santiago de Cali case

Objetivo: establecer la relación entre los determinantes sociales de la salud y la discapacidad en Santiago de Cali. Metodología: estudio descriptivo correlacional. Se incluyeron para el análisis 38.071 personas registradas en la base de datos del Dane (Cali); la información se procesó en SPSS 19.0: determinantes estructurales, género, edad, nivel educativo, raza, zona de residencia, estrato y determinantes intermedios como trabajo y vivienda; se realizó análisis univariado y bivariado empleando la prueba de x2 . Resultados: el 52% de las personas pertenecía al género femenino; el promedio de la edad fue de 48 años +/– 24,1 años y la raza predominante, la mestiza. El 28% de las personas registradas no tenía ningún nivel de estudio; un 76% de las personas pertenecen a estratos 1 y 2. El 100% tienen al menos una deficiencia y una discapacidad y el 25% presentan restricción en la participación. El género femenino presenta menos restricción en la participación, comparado con el masculino (71,2% y 66,8% respectivamente). Se encontró asociación entre los determinantes sociales estructurales e intermedios y la restricción en la participación p < 0,05. Conclusiones: existe interacción de los determinantes sociales de la salud, como género, educación, empleo, barreras arquitectónicas y servicios de salud, entre otros, con la restricción en la participación Objective: to establish the relationship between the social determinants of health and disability in Santiago de Cali. Methodology: a correlational descriptive study. The analysis included a total of 38,071 people who had been registered in the dane database (Cali), and the data was processed using the spss 19.0 software. Structural Determinants: gender, age, education level, race, area of residence, and intermediate determinants such as job and housing information. In addition, univariate and bivariate analyses were conducted using the x2 test. Results: of the participants, 52% were female, the average age was 48 years +/- 24.1 years, the predominant race was mestizo and 28% of the respondents said they had no studies. Moreover, 100% of the respondents had at least one form of impairment or disability, and 25% of them had some restriction regarding social participation. The female participants had less restrictions regarding social participation than males (71.2% vs. 66.8%), and there was a correlation between the social structural and intermediate determinants and the restrictions in participation p <0.05. Conclusions: there is interaction between Social Determinants of Health such as gender, education, employment, architectural barriers, health services, etc. and the restrictions in participatio

Exploring the link between MORF4L1 and risk of breast cancer

Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers