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| 2. |
- Aguiar, A., et al.
(författare)
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Practices in prescribing protein substitutes for PKU in Europe : No uniformity of approach
- 2015
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Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192 .- 1096-7206. ; 115:1, s. 17-22
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Tidskriftsartikel (refereegranskat)abstract
- Background: There appears little consensus concerning protein requirements in phenylketonuria (PKU). Methods: A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics. Results: The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n = 24 centres) (infants <1 year, >2-3 g/kg/day; 1-3 years of age, >2-3 g/kg/day; 4-10 years of age, >1.5-2.5 g/kg/day) and Southern Europe (n = 10 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, 2 g/kg/day; 4-10 years of age, 1.5-2 g/kg/day), than by Eastern Europe (n = 4 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, >2-2.5 g/kg/day; 4-10 years of age, >1.5-2 g/kg/day) and with Western Europe (n = 25 centres) giving the least (infants <1 year, >2-2.5 g/kg/day, 1-3 years of age, 1.5-2 g/kg/day; 4-10 years of age, 1-1.5 g/kg/day). Total protein prescription was similar in patients aged >10 years (1-1.5 g/kg/day) and maternal patients (1-1.5 g/kg/day). Conclusions: The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population.
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- Venkatesan, M, et al.
(författare)
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Erratum
- 2019
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Ingår i: The American journal of tropical medicine and hygiene. - : American Society of Tropical Medicine and Hygiene. - 1476-1645 .- 0002-9637. ; 100:3, s. 766-766
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Broadaway, K Alaine, et al.
(författare)
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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
- 2023
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Ingår i: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299
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Tidskriftsartikel (refereegranskat)abstract
- Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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| 10. |
- Schrieks, I. C., et al.
(författare)
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Adiponectin, Free Fatty Acids, and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Acute Coronary Syndrome
- 2018
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 41:8, s. 1792-1800
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE In observational cohorts, adiponectin is inversely associated and free fatty acids (FFAs) are directly associated with incident coronary heart disease (CHD). Adiponectin tends to be reduced and FFAs elevated in type 2 diabetes. We investigated relationships of adiponectin and FFA and major adverse cardiovascular events (MACEs) and death in patients with acute coronary syndrome (ACS) and type 2 diabetes using data from the AleCardio (Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus) trial, which compared the PPAR-alpha/gamma agonist aleglitazar with placebo. Using Cox regression adjusted for demographic, laboratory, and treatment variables, we determined associations of baseline adiponectin and FFAs, or the change in adiponectin and FFAs from baseline, with MACEs (cardiovascular death, myocardial infarction, or stroke) and death. A twofold higher baseline adiponectin (n = 6,998) was directly associated with risk of MACEs (hazard ratio [HR] 1.17 [95% CI 1.08-1.27]) and death (HR 1.53 [95% CI 1.35-1.73]). A doubling of adiponectin from baseline to month 3 (n = 6,325) was also associated with risk of death (HR 1.20 [95% CI 1.03-1.41]). Baseline FFAs (n = 7,038), but not change in FFAs from baseline (n = 6,365), were directly associated with greater risk of MACEs and death. There were no interactions with study treatment. In contrast to prior observational data for incident CHD, adiponectin is prospectively associated with MACEs and death in patients with type 2 diabetes and ACS, and an increase in adiponectin from baseline is directly related to death. These findings raise the possibility that adiponectin has different effects in patients with type 2 diabetes and ACS than in populations without prevalent cardiovascular disease. Consistent with prior data, FFAs are directly associated with adverse outcomes.
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| 11. |
- Stahli, B. E., et al.
(författare)
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Homeostasis Model Assessment of Insulin Resistance and Survival in Patients With Diabetes and Acute Coronary Syndrome
- 2018
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:7, s. 2522-2533
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Insulin resistance has been linked to development and progression of atherosclerosis and is present in most patients with type 2 diabetes. Whether the degree of insulin resistance predicts adverse outcomes in patients with type 2 diabetes and acute coronary syndrome (ACS) is uncertain. Design: The Effect of Aleglitazar on Cardiovascular Outcomes after Acute Coronary Syndrome in Patients with Type 2 Diabetes Mellitus trial compared the peroxisome proliferator-activated receptor-a/g agonist aleglitazar with placebo in patients with type 2 diabetes and recent ACS. In participants not treated with insulin, we determined whether baseline homeostasis model assessment of insulin resistance (HOMA-IR; n = 4303) or the change in HOMA-IR on assigned study treatment (n = 3568) was related to the risk of death or major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in unadjusted and adjusted models. Because an inverse association of HOMA-IR with N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been described, we specifically examined effects of adjustment for the latter. Results: In unadjusted analysis, twofold higher baseline HOMA-IR was associated with lower risk of death [hazard ratio (HR): 0.79, 95% CI: 0.68 to 0.91, P = 0.002]. Adjustment for 24 standard demographic and clinical variables had minimal effect on this association. However, after further adjustment for NT-proBNP, the association of HOMA-IR with death was no longer present (adjusted HR: 0.99, 95% CI: 0.83 to 1.19, P = 0.94). Baseline HOMA-IR was not associated with major adverse cardiovascular events, nor was the change in HOMA-IR on study treatment associated with death or major adverse cardiovascular events. Conclusions: After accounting for levels of NT-proBNP, insulin resistance assessed by HOMA-IR is not related to the risk of death or major adverse cardiovascular events in patients with type 2 diabetes and ACS.
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- Medina, LMP, et al.
(författare)
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Targeted plasma proteomics reveals signatures discriminating COVID-19 from sepsis with pneumonia
- 2023
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Ingår i: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X. ; 24:1, s. 62-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCOVID-19 remains a major public health challenge, requiring the development of tools to improve diagnosis and inform therapeutic decisions. As dysregulated inflammation and coagulation responses have been implicated in the pathophysiology of COVID-19 and sepsis, we studied their plasma proteome profiles to delineate similarities from specific features.MethodsWe measured 276 plasma proteins involved in Inflammation, organ damage, immune response and coagulation in healthy controls, COVID-19 patients during acute and convalescence phase, and sepsis patients; the latter included (i) community-acquired pneumonia (CAP) caused by Influenza, (ii) bacterial CAP, (iii) non-pneumonia sepsis, and (iv) septic shock patients.ResultsWe identified a core response to infection consisting of 42 proteins altered in both COVID-19 and sepsis, although higher levels of cytokine storm-associated proteins were evident in sepsis. Furthermore, microbiologic etiology and clinical endotypes were linked to unique signatures. Finally, through machine learning, we identified biomarkers, such as TRIM21, PTN and CASP8, that accurately differentiated COVID-19 from CAP-sepsis with higher accuracy than standard clinical markers.ConclusionsThis study extends the understanding of host responses underlying sepsis and COVID-19, indicating varying disease mechanisms with unique signatures. These diagnostic and severity signatures are candidates for the development of personalized management of COVID-19 and sepsis.
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| 22. |
- Finsterle, S., et al.
(författare)
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Conceptual uncertainties in modelling the interaction between engineered and natural barriers of nuclear waste repositories in crystalline rocks
- 2019
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Ingår i: Geological Society Special Publication. - 0305-8719. ; 482:1, s. 261-283
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear waste disposal in geological formations relies on a multi-barrier concept that includes engineered components – which, in many cases, include a bentonite buffer surrounding waste packages – and the host rock. Contrasts in materials, together with gradients across the interface between the engineered and natural barriers, lead to complex interactions between these two subsystems. Numerical modelling, combined with monitoring and testing data, can be used to improve our overall understanding of rock–bentonite interactions and to predict the performance of this coupled system. Although established methods exist to examine the prediction uncertainties due to uncertainties in the input parameters, the impact of conceptual model decisions on the quantitative and qualitative modelling results is more difficult to assess. A Swedish Nuclear Fuel and Waste Management Company Task Force project facilitated such an assessment. In this project, 11 teams used different conceptualizations and modelling tools to analyse the Bentonite Rock Interaction Experiment (BRIE) conducted at the Äspö Hard Rock Laboratory in Sweden. The exercise showed that prior system understanding along with the features implemented in the available simulators affect the processes included in the conceptual model. For some of these features, sufficient characterization data are available to obtain defensible results and interpretations, whereas others are less supported. The exercise also helped to identify the conceptual uncertainties that led to different assessments of the relative importance of the engineered and natural barrier subsystems. The range of predicted bentonite wetting times encompassed by the ensemble results were considerably larger than the ranges derived from individual models. This is a consequence of conceptual uncertainties, demonstrating the relevance of using a multi-model approach involving alternative conceptualizations.
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| 25. |
- Kiviniemi, T., et al.
(författare)
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A randomized prospective multicenter trial for stroke prevention by prophylactic surgical closure of the left atrial appendage in patients undergoing bioprosthetic aortic valve surgery––LAA-CLOSURE trial protocol
- 2021
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 237, s. 127-134
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Tidskriftsartikel (refereegranskat)abstract
- Patients undergoing surgical aortic valve replacement (SAVR) are at high risk for atrial fibrillation (AF) and stroke after surgery. There is an unmet clinical need to improve stroke prevention in this patient population. The LAA-CLOSURE trial aims to assess the efficacy and safety of prophylactic surgical closure of the left atrial appendage for stroke and cardiovascular death prevention in patients undergoing bioprosthetic SAVR. This randomized, open-label, prospective multicenter trial will enroll 1,040 patients at 13 European sites. The primary endpoint is a composite of cardiovascular mortality, stroke and systemic embolism at 5 years. Secondary endpoints include cardiovascular mortality, stroke, systemic embolism, bleed fulfilling academic research consortium (BARC) criteria, hospitalization for decompensated heart failure and health economic evaluation. Sample size is based on 30% risk reduction in time to event analysis of primary endpoint. Prespecified reports include 30-day safety analysis focusing on AF occurrence and short-term outcomes and interim analyses at 1 and 3 years for primary and secondary outcomes. Additionally, substudies will be performed on the completeness of the closure using transesophageal echocardiography/cardiac computed tomography and long-term ECG recording at one year after the operation. © 2021 The Author(s)
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| 26. |
- Lindman, Henrik, et al.
(författare)
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A randomised study of tailored toxicity-based dosage of fluorouracil-epirubicin-cyclophosphamide chemotherapy for early breast cancer (SBG 2000-1)
- 2018
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 94, s. 79-86
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Tidskriftsartikel (refereegranskat)abstract
- Study aim: Retrospective studies have demonstrated a worse outcome in breast cancer patients not developing leukopenia during adjuvant chemotherapy. The SBG 2000-1 is the first randomised trial designed to compare individually dosed chemotherapy without G-CSF support based on grade of toxicity to standard-dosed chemotherapy based on body surface area (BSA). Methods: Patients with early breast cancer were included and received the first cycle of standard FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2). Patients with nadir leukopenia grade 0–2 after first cycle were randomised between either 6 additional courses of tailored FEC with increased doses (E 75–90 mg/m2, C 900–1200 mg/m2) or fixed treatment with 6 standard FEC. Patients with grade 3–4 leukopenia were registered and treated with 6 standard FEC. Primary end-point was distant disease-free survival (DDFS). Results: The study enrolled 1535 patients, of which 1052 patients were randomised to tailored FEC (N = 524) or standard FEC (N = 528), whereas 401 patients with leukopenia grade 3–4 continued standard FEC and formed the registered cohort. Dose escalation did not statistically significantly improve 10-year DDFS (79% and 77%, HR 0.87, CI 0.67–1.14, P = 0.32) or OS (82% and 78%, respectively, HR 0.89, CI 0.57–1.16, P = 0.38). Corresponding estimates for the registered group of patients were DDFS 79% and OS 82%, respectively. Conclusions: The SBG 2000-1 study failed to show a statistically significant improvement of escalated and tailored-dosed chemotherapy compared with standard BSA-based chemotherapy in patients with low haematological toxicity, although all efficacy parameters showed a numerical advantage for tailored treatment.
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| 35. |
- Dekker, Joost, et al.
(författare)
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Definition and Characteristics of Behavioral Medicine, and Main Tasks and Goals of the International Society of Behavioral Medicine : an International Delphi Study
- 2021
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Ingår i: International Journal of Behavioral Medicine. - New York : Springer. - 1070-5503 .- 1532-7558. ; 28:3, s. 268-276
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the past decades, behavioral medicine has attained global recognition. Due to its global reach, a critical need has emerged to consider whether the original definition of behavioral medicine is still valid, comprehensive, and inclusive, and to reconsider the main tasks and goals of the International Society of Behavioral Medicine (ISBM), as the umbrella organization in the field. The purpose of the present study was to (i) update the definition and scope of behavioral medicine and its defining characteristics; and (ii) develop a proposal on ISBM's main tasks and goals.Method: Our study used the Delphi method. A core group prepared a discussion paper. An international Delphi panel rated questions and provided comments. The panel intended to reach an a priori defined level of consensus (i.e., 70%).Results: The international panel reached consensus on an updated definition and scope of behavioral medicine as a field of research and practice that builds on collaboration among multiple disciplines. These disciplines are concerned with development and application of behavioral and biomedical evidence across the disease continuum in clinical and public health domains. Consensus was reached on a proposal for ISBM's main tasks and goals focused on supporting communication and collaboration across disciplines and participating organizations; stimulating research, education, and practice; and supporting individuals and organizations in the field.Conclusion: The consensus on definition and scope of behavioral medicine and ISBM's tasks and goals provides a foundational step toward achieving these goals.
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| 40. |
- Menon, U, et al.
(författare)
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Time intervals and routes to diagnosis for lung cancer in 10 jurisdictions: cross-sectional study findings from the International Cancer Benchmarking Partnership (ICBP)
- 2019
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 9:11, s. e025895-
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Tidskriftsartikel (refereegranskat)abstract
- Differences in time intervals to diagnosis and treatment between jurisdictions may contribute to previously reported differences in stage at diagnosis and survival. The International Cancer Benchmarking Partnership Module 4 reports the first international comparison of routes to diagnosis and time intervals from symptom onset until treatment start for patients with lung cancer.DesignNewly diagnosed patients with lung cancer, their primary care physicians (PCPs) and cancer treatment specialists (CTSs) were surveyed in Victoria (Australia), Manitoba and Ontario (Canada), Northern Ireland, England, Scotland and Wales (UK), Denmark, Norway and Sweden. Using Wales as the reference jurisdiction, the 50th, 75th and 90th percentiles for intervals were compared using quantile regression adjusted for age, gender and comorbidity.ParticipantsConsecutive newly diagnosed patients with lung cancer, aged ≥40 years, diagnosed between October 2012 and March 2015 were identified through cancer registries. Of 10 203 eligible symptomatic patients contacted, 2631 (27.5%) responded and 2143 (21.0%) were included in the analysis. Data were also available from 1211 (56.6%) of their PCPs and 643 (37.0%) of their CTS.Primary and secondary outcome measuresInterval lengths (days; primary), routes to diagnosis and symptoms (secondary).ResultsWith the exception of Denmark (−49 days), in all other jurisdictions, the median adjusted total interval from symptom onset to treatment, for respondents diagnosed in 2012–2015, was similar to that of Wales (116 days). Denmark had shorter median adjusted primary care interval (−11 days) than Wales (20 days); Sweden had shorter (−20) and Manitoba longer (+40) median adjusted diagnostic intervals compared with Wales (45 days). Denmark (−13), Manitoba (−11), England (−9) and Northern Ireland (−4) had shorter median adjusted treatment intervals than Wales (43 days). The differences were greater for the 10% of patients who waited the longest. Based on overall trends, jurisdictions could be grouped into those with trends of reduced, longer and similar intervals to Wales. The proportion of patients diagnosed following presentation to the PCP ranged from 35% to 75%.ConclusionThere are differences between jurisdictions in interval to treatment, which are magnified in patients with lung cancer who wait the longest. The data could help jurisdictions develop more focused lung cancer policy and targeted clinical initiatives. Future analysis will explore if these differences in intervals impact on stage or survival.
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| 43. |
- Språngberg, A, et al.
(författare)
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SBU. Godartad prostataförstoring med avflödeshinder. En systematisk litteraturöversikt : Godartad prostataförstoring med avflödeshinder
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Slutsatser Godartad prostataförstoring (benign prostatahyperplasi, BPH) är ett vanligt tillstånd som med stigande ålder drabbar i princip alla män. En del av dessa män får urineringsproblem och cirka 4 500 opereras varje år för en förstorad prostata. Många med lindrigare besvär behandlas med läkemedel eller behöver ingen behandling alls. Avflödeshinder kan obehandlat ge allvarlig urinretention som skadar njurarna, och en urinstämma kan vara livshotande. För att avgränsa den grupp av män där problemen med urineringen beror på en förstorad prostata används ett tiotal olika diagnostiska metoder. När det gäller behandling finns det flera olika kirurgiska metoder, varav några är väl etablerade och andra av mer experimentell karaktär. Under 1990-talet har också flera läkemedel introducerats. SBU har därför bedömt att det funnits ett behov av att göra en systematisk genomgång av den vetenskapliga grunden för dessa olika metoder. Nedan följer de viktigaste slutsatserna av arbetet.
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| 44. |
- Vallon-Christersson, J., et al.
(författare)
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RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer
- 2022
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 33:Suppl 3, s. 144-145
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Konferensbidrag (refereegranskat)abstract
- BackgroundMultigene expression assays for molecular subtypes and biomarkers can aid clinical management of early invasive breast cancer. Based on RNA-sequencing we aimed to develop single-sample predictor (SSP) models for conventional clinical markers, molecular intrinsic subtype and risk of recurrence (ROR).MethodsA uniformly accrued breast cancer cohort of 7743 patients with RNA-sequencing data from fresh tissue was divided into a training set and a reserved test set. We trained SSPs for PAM50 molecular subtypes and ROR assigned by nearest-centroid (NC) and SSPs for conventional clinical markers from histopathology data. Additionally, SSP classifications were compared with Prosigna® in two external cohorts. Prognostic value was assessed using distant recurrence-free interval.ResultsIn the test set, agreement between SSP and NC classifications for PAM50 (five subtypes) and Subtype (four subtypes) was high (85%, Kappa=0.78) and very high (90%, Kappa=0.84) respectively. Accuracy for ROR risk category was high (84%, Kappa=0.75, weighted Kappa=0.90). The prognostic value for SSP and NC was assessed as equivalent. Agreement for SSP and histopathology was very high or high for receptor status, while moderate and poor for Ki67 status and Nottingham histological grade, respectively. SSP concordance with Prosigna® was high for subtype and moderate and high for ROR risk category. In pooled analysis, concordance between SSP and Prosigna® for emulated treatment recommendation for chemotherapy (yes vs. no) was high (85%, Kappa=0.66). In postmenopausal ER+/HER2-/N0 patients SSP application suggested changed treatment recommendations for up to 17% of patients, with nearly balanced escalation and de-escalation of chemotherapy.ConclusionsSSP models for histopathological variables, PAM50, and ROR classifications can be derived from RNA-sequencing that closely matches clinical tests. Agreement and outcome analyses suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level. Retrospective evaluation in postmenopausal ER+/HER2-/N0 patients suggested that molecular testing could lead to a changed therapy recommendation for almost one-fifth of patients.
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| 45. |
- Venkatesan, Meera, et al.
(författare)
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Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes : parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.
- 2014
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Ingår i: The American journal of tropical medicine and hygiene. - : American Society of Tropical Medicine and Hygiene. - 1476-1645 .- 0002-9637. ; 91:4, s. 833-43
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Tidskriftsartikel (refereegranskat)abstract
- Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.
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| 47. |
- Winter, C, et al.
(författare)
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Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic
- 2016
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 27:8, s. 8-1532
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear.PATIENTS AND METHODS: Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden.RESULTS: Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years).CONCLUSIONS: In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling.
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