We characterized the expression of BRCA1 and BRCA2 in 38 sporadic colorectal carcinomas and matched normal mucosas with 9 anti-BRCA1 antibodies and 4 anti-BRCA2 antibodies, raised against several different epitopes, using immunohistochemical technique. We demonstrated an increased BRCA1 and BRCA2 staining in the apical cell pole of epithelial malignant cells and we also revealed a significant increase in BRCA1 and BRCA2 nuclear foci in tumor colorectal specimens in comparison with corresponding normal tissues. These increases in BRCA1 and BRCA2 expression may be explained by the fact that colorectal tissue is subject to very active proliferation and differentiation.
ABSTRACT Pharmacogenetic studies involving Carboxylesterase 1 (CES1), Latrophilin‐3 (LPHN3), and Catechol‐O‐methyltransferase (COMT) revealed individual differences regarding therapeutic response in children with attention deficit hyperactivity disorder (ADHD) under methylphenidate (MPH) treatment. This study aimed to evaluate MPH's association with the adverse effect status in children and its relationship with CES1, LPHN3, and COMT in the Turkish population. The study included 102 children and adolescents with ADHD, who were categorized as responders, or the adverse effect group based on their treatment response. The Naranjo Adverse Drug Reaction Probability Scale evaluated the presence and severity of adverse effects. Saliva sample was taken from the patients and genotype distribution of CES1 rs3815583, CES1 rs2307227, LPHN3 rs6551665, LPHN3 rs1947274, LPHN3 rs6858066, LPHN3 rs2345039, and COMT rs4680 were examined. In the adverse effect group, instances of carrying the GG genotype in CES1 rs2307227, having G vs. T genotype and GG vs. GT were significantly higher. In LPHN3 rs2345039, carrying the C genotype vs. G was associated with a serious adverse effect. In COMT rs4680, individuals with the AA or GG genotype were significantly higher in the adverse effect group. Our study suggests a relationship between genetic polymorphisms and the side effect status in children receiving MPH.
Abstract Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction can lead to timely intervention and better outcomes. Through summary statistics of meta-analyses of published genome-wide association studies performed in over 1.2 million of individuals, we combined 9 PRS gathering genomic variants associated to cardiovascular and renal diseases and their key risk factors into one logistic regression model, to predict micro- and macrovascular endpoints of diabetes. Its clinical utility in predicting complications of diabetes was tested in 4098 participants with diabetes of the ADVANCE trial followed during a period of 10 years and replicated it in three independent non-trial cohorts. The prediction model adjusted for ethnicity, sex, age at onset and diabetes duration, identified the top 30% of ADVANCE participants at 3.1-fold increased risk of major micro- and macrovascular events (p=6.3×10 −21 and p=9.6×10 −31 , respectively) and at 4.4-fold (p=6.8×10 −33 ) increased risk of cardiovascular death compared to the remainder of T2D subjects. While in ADVANCE overall, combined intensive therapy of blood pressure and glycaemia decreased cardiovascular mortality by 24%, the prediction model identified a high-risk group in whom this therapy decreased mortality by 47%, and a low risk group in whom the therapy had no discernable effect. Patients with high PRS had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. This novel polygenic prediction model identified people with diabetes at low and high risk of complications and improved targeting those at greater benefit from intensive therapy while avoiding unnecessary intensification in low-risk subjects.
Introduction: We assessed the performance of our newly developed polygenic risk score (PRS) to predict microvascular and macrovascular complications of type 2 diabetes (T2D) in men and women. The PRS is composed of 600 common genomic variants associated to diabetes, cardiovascular and renal diseases and their key risk factors selected from summary statistics of meta-analyses of published genome-wide association studies performed in over 1.2 million of individuals. The performance of the polygenic model was assessed by c-statistics in 4098 genotyped participants of European descent of the ADVANCE trial (46.4% women) followed during a period of five years. Methods: The logistic regression model that included the PRS adjusted for the principal component (PC1) of genetically determined ancestry, age at diagnosis and T2D duration, and treatment assignment, did not include any clinical or outcome data. Results: The discrimination between cases (having a specific complication) from controls (free of this complication) at entry in ADVANCE had AUCs for microvascular complications of 0.63 (0.60-0.65) in men and 0.66 (0.63-0.69) in women, sex differences p = 0.07. AUCs for macrovascular complications were 0.56 (0.54-0.58) in men and 0.57 (0.54-0.61) in women; p = 0.41. The AUCs for prediction of incident cases, defined as having an outcome during the ADVANCE trial (free of outcome at baseline) compared to controls that did not have a specific outcome at any time during the study, were for microvascular events 0.66 (0.63-0.70) in men and 0.71 (0.66-0.77) in women; p = 0.15. AUCs for macrovascular events were 0.65 (0.62-0.68) and 0.72 (0.68-0.76) respectively, p = 0.01. AUC for prediction of cardiovascular death occurring during the trial was 0.71 (0.67-0.75) in men and 0.77 (0.72-0.82) in women; p = 0.04. Conclusion: Our polygenic model demonstrated an overall better performance in women than in men and a better prediction capacity in individuals free of previous events in both sexes. Disclosure J. Tremblay: Research Support; Self; Servier. Stock/Shareholder; Self; OPTITHERA. R. Attaoua: None. M. Haloui: None. R. Tahir: None. C. Long: None. C. Hizel: None. J. Chalmers: None. S. Harrap: None. M. Woodward: Consultant; Self; Amgen, Kyowa Hakko Kirin Co., Ltd. P. Hamet: Research Support; Self; Servier. Stock/Shareholder; Self; OPTITHERA. Funding Genome Quebec; Canadian Institutes of Health Research; MEIE; CQDM; Opti Thera; Servier, Canada Research Chair in Predictive Genomics
The localization of BRCA1 protein was studied in 49 sporadic breast carcinomas for which allelic losses of BRCA1 have been investigated. One group consisted of 15 breast carcinomas having one allelic loss of BRCA1 and the other group of 34 breast carcinomas with no allelic loss of BRCA1. The localization of BRCA1 in the 2 groups was performed using polyclonal antibodies (K-18; C-20; D-20; I-20) raised against BRCA1 and by comparing frozen and paraffin-embedded tissues. We show that no correlation was found between the expression of BRCA1 protein and allelic loss of BRCA1. But, the nuclear detection of BRCA1 in frozen samples was improved when compared to paraffinized ones.
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