The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Background: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. Methods: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. Results: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93–1.10, Ptrend=0.77; MDM2: HR=0.96, 95%CI: 0.84–1.09, Ptrend=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87–1.12, Ptrend=0.83; MDM2: HR=0.98, 95%CI: 0.80–1.21, Ptrend=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. Conclusion: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers. O M Sinilnikova1,2, A C Antoniou3, J Simard4, S Healey5, M Léoné1, D Sinnett6,7, A B Spurdle5, J Beesley5, X Chen5, kConFab8, M H Greene9, J T Loud9, F Lejbkowicz10, G Rennert10, S Dishon10, I L Andrulis11,12, OCGN11, S M Domchek13, K L Nathanson13, S Manoukian14, P Radice15,16, I Konstantopoulou17, I Blanco18, A L Laborde19, M Durán20, A Osorio21, J Benitez21, U Hamann22, F B L Hogervorst23, T A M van Os24, H J P Gille25, HEBON23, S Peock3, M Cook3, C Luccarini26, D G Evans27, F Lalloo27, R Eeles28, G Pichert29, R Davidson30, T Cole31, J Cook32, J Paterson33, C Brewer34, EMBRACE3, D J Hughes35, I Coupier36,37, S Giraud1, F Coulet38, C Colas38, F Soubrier38, E Rouleau39, I Bièche39, R Lidereau39, L Demange40, C Nogues40, H T Lynch41, GEMO1,2,42, R K Schmutzler43, B Versmold43, C Engel44, A Meindl45, N Arnold46, C Sutter47, H Deissler48, D Schaefer49, U G Froster50, GC-HBOC43,44,45,46,47,48,49,50, K Aittomäki51, H Nevanlinna52, L McGuffog3, D F Easton3, G Chenevix-Trench5 and D Stoppa-Lyonnet42 on behalf of the Consortium of Investigators of Modifiers of BRCA1/

Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.Peer reviewe

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Intravenous Tranexamic Acid Versus Topical Aminocaproic Acid: Which Method Has the Least Blood Loss and Transfusion Rates?

IntroductionSince the advent of antifibrinolytics, blood transfusions and their associated complications in total joint arthroplasty have decreased. Few studies have compared different antifibrinolytic types with respect to blood loss and transfusion rates. We sought to compare the blood loss and transfusion rates between epsilon-aminocaproic acid (EACA), tranexamic acid (TXA), and control.MethodsA total of 564 patients underwent primary total hip or total knee arthroplasty at our institution. Patients were divided into 3 groups: 183 EACA, 204 TXA, and 177 control. Patient demographics, hemoglobin, transfusion rates, and blood loss were collected.ResultsPatient preoperative variables were similar. The control group had a mean estimated blood loss (EBL) of 1.48 L, with 51 units of packed red blood cells (pRBCs) given and 14.7% of patients receiving a blood transfusion. The EACA group had an EBL of 1.33 L, with 20 pRBCs given and 10.9% of patients receiving a transfusion. The TXA group had an EBL of 1.05 L, with 3 pRBCs transfused in 0.98% of patients. Compared with the control group, blood loss (P = 0.0014; P < 0.0001), number of pRBCs given (P = 0.007; P < 0.0001), and number of patients transfused (P = 0.012; P < 0.0001) were significantly lower in the EACA and TXA groups, respectively. TXA had significantly lower blood loss (P < 0.0001), lower number of tranfusions (P = 0.005), and less patients transfused (P = 0.003) compared with EACA.ConclusionOur study reports lower blood loss, transfusion rates, and number of patients needing transfusion with both EACA and TXA in the setting of total joint arthroplasty. When comparing between EACA and TXA, TXA had lower blood loss, transfusion rates, and number of patients requiring transfusion

Manual versus Mechanical Delivery of High-Quality Cardiopulmonary Resuscitation on a River-Based Fire Rescue Boat.

ObjectivesStudies have demonstrated the efficacy of mechanical devices at delivering high-quality cardiopulmonary resuscitation (HQ-CPR) in various transport settings. Herein, this study investigates the efficacy of manual and mechanical HQ-CPR delivery on a fire rescue boat.MethodsA total of 15 active firefighter-paramedics were recruited for a prospective manikin-based trial. Each paramedic performed two minutes manual compression-only CPR while navigating on a river-based fire rescue boat. The boat was piloted in either a stable linear manner or dynamic S-turn manner to simulate obstacle avoidance. For each session of manual HQ-CPR, a session of mechanical HQ-CPR was also performed with a LUCAS 3 (Stryker; Kalamazoo, Michigan USA). A total of 60 sessions were completed. Parameters recorded included compression fraction (CF) and the percentage of compressions with correct depth >5cm (D%), correct rate 100-120 (R%), full release (FR%), and correct hand position (HP%). A composite HQ-CPR score was calculated as follows: ((D% + R% + FR% + HP%)/4) * CF%). Differences in magnitude of change seen in stable versus dynamic navigation within study conditions were evaluated with a Z-score calculation. Difficulty of HQ-CPR delivery was assessed utilizing the Borg Rating of Perceived Exertion Scale.ResultsParticipants were mostly male and had a median experience of 20 years. Manual HQ-CPR delivered during stable navigation out-performed manual HQ-CPR delivered during dynamic navigation for composite score and trended towards superiority for FR% and R%. There was no difference seen for any measured variable when comparing mechanical HQ-CPR delivered during stable navigation versus dynamic navigation. Mechanical HQ-CPR out-performed manual HQ-CPR during both stable and dynamic navigation in terms of composite score, FR%, and R%. Z-score calculation demonstrated that manual HQ-CPR delivery was significantly more affected by drive style than mechanical HQ-CPR delivery in terms of composite HQ-CPR score and trended towards significance for FR% and R%. Borg Rating of Perceived Exertion was higher for manual CPR delivered during dynamic sessions than for stable sessions.ConclusionMechanical HQ-CPR delivery is superior to manual HQ-CPR delivery during both stable and dynamic riverine navigation. Whereas manual HQ-CPR delivery was worse during dynamic transportation conditions compared to stable transport conditions, mechanical HQ-CPR delivery was unaffected by drive style. This suggests the utility of routine use of mechanical HQ-CPR devices in the riverine patient transport setting

Mortality and Complication Rates in Adult Trauma Patients Receiving Tranexamic Acid: A Single-center Experience in the Post-CRASH-2 Era.

OBJECTIVES:The CRASH-2 trial demonstrated that tranexamic acid (TXA) in adults with significant traumatic hemorrhage safely reduces mortality. Given that the CRASH-2 trial did not include U.S. sites, our objective was to evaluate patient characteristics, TXA dosing strategies, and the incidence of mortality and adverse events in adult trauma patients receiving TXA at a U.S. Level I trauma center in the post-CRASH-2 era. METHODS:We conducted a retrospective study that included patients aged 18 years or older who received TXA after an acute injury from July 2014 to June 2017. We excluded patients who received TXA orally, patients who received TXA for elective surgical procedures or nontrauma indications, patients who received it 8 hours or longer after the time of injury, and patients with cardiac arrest at time of emergency department arrival. Trained abstractors collected data from the trauma registry and hospital electronic medical records. Our primary outcome measures were in-hospital death and acute thromboembolic events within 28 days from injury. RESULTS:We included 273 patients with a mean (±SD) age of 43.8 (±18.7)  years. The mean (±SD) time of administration of TXA from time of injury was 1.55 (±1.2)  hours with 229 patients (83.9%) receiving TXA within 3 hours. The overall mortality within 28 days from injury was 12.8% (95% confidence interval [CI] = 8.9% to 16.7%), which was similar compared to that in the CRASH-2 trial (14.5%, 95% CI = 13.9% to 15.2%). The incidence of acute thromboembolic events was 6.6% (95% CI = 3.7% to 9.5%), which was higher than that in the CRASH-2 trial (2.0%, 95% CI = 1.73% to 2.27%). Patients in our cohort also received surgery (64.8% vs. 47.9%) and blood transfusions (74.0% vs. 50.4%) more frequently than those in the CRASH-2 cohort. CONCLUSIONS:Adult trauma patients receiving TXA had similar incidences of death but higher incidences of thromboembolic events compared to the CRASH-2 trial. Variation in patient characteristics, injury severity, TXA dosing, and surgery and transfusion rates could explain these observed differences. Further research is necessary to provide additional insight into the incidence and risk factors of thromboembolic events in TXA use

Mortality and Complication Rates in Adult Trauma Patients Receiving Tranexamic Acid: A Single-center Experience in the Post-CRASH-2 Era.

OBJECTIVES:The CRASH-2 trial demonstrated that tranexamic acid (TXA) in adults with significant traumatic hemorrhage safely reduces mortality. Given that the CRASH-2 trial did not include U.S. sites, our objective was to evaluate patient characteristics, TXA dosing strategies, and the incidence of mortality and adverse events in adult trauma patients receiving TXA at a U.S. Level I trauma center in the post-CRASH-2 era. METHODS:We conducted a retrospective study that included patients aged 18 years or older who received TXA after an acute injury from July 2014 to June 2017. We excluded patients who received TXA orally, patients who received TXA for elective surgical procedures or nontrauma indications, patients who received it 8 hours or longer after the time of injury, and patients with cardiac arrest at time of emergency department arrival. Trained abstractors collected data from the trauma registry and hospital electronic medical records. Our primary outcome measures were in-hospital death and acute thromboembolic events within 28 days from injury. RESULTS:We included 273 patients with a mean (±SD) age of 43.8 (±18.7)  years. The mean (±SD) time of administration of TXA from time of injury was 1.55 (±1.2)  hours with 229 patients (83.9%) receiving TXA within 3 hours. The overall mortality within 28 days from injury was 12.8% (95% confidence interval [CI] = 8.9% to 16.7%), which was similar compared to that in the CRASH-2 trial (14.5%, 95% CI = 13.9% to 15.2%). The incidence of acute thromboembolic events was 6.6% (95% CI = 3.7% to 9.5%), which was higher than that in the CRASH-2 trial (2.0%, 95% CI = 1.73% to 2.27%). Patients in our cohort also received surgery (64.8% vs. 47.9%) and blood transfusions (74.0% vs. 50.4%) more frequently than those in the CRASH-2 cohort. CONCLUSIONS:Adult trauma patients receiving TXA had similar incidences of death but higher incidences of thromboembolic events compared to the CRASH-2 trial. Variation in patient characteristics, injury severity, TXA dosing, and surgery and transfusion rates could explain these observed differences. Further research is necessary to provide additional insight into the incidence and risk factors of thromboembolic events in TXA use

A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 × 10⁻⁹ to P(trend) = 3.9 × 10⁻⁷), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 × 10⁻⁷) to P(trend) = 8 × 10⁻⁵; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 × 10⁻

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

<p>TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.</p>