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The impact of anti-thymocyte globulin on the outcomes of Patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation.

La, 16/11/2019 - 23:02
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The impact of anti-thymocyte globulin on the outcomes of Patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation.

Leukemia. 2019 Nov 14;:

Authors: Nagler A, Dholaria B, Labopin M, Socie G, Huynh A, Itälä-Remes M, Deconinck E, Yakoub-Agha I, Cahn JY, Bourhis JH, Labussière-Wallet H, Chantepie S, Esteve J, Savani B, Mohty M

Abstract
Measurable residual disease (MRD) status pre-allogeneic hematopoietic cell transplantation (allo-HCT) has been shown to predict transplant outcomes. We investigated the effect of Anti-Thymocyte Globulin (ATG) on acute myelogenous leukemia (AML) relapse by pretransplant MRD status. AML patients undergoing allo-HCT in first complete remission from either a matched sibling or unrelated donor during the 2006-2017 period were selected. Outcomes of 1509 patients (MRD+, n = 426) were studied. ATG was used in 561 (52%) and 239 (58%) patients within the MRD- and MRD+ cohorts, respectively. In MRD- patients, ATG did not affect relapse incidence (RI) (HR = 0.80, p = 0.17), but was associated with reduced incidence of grade II-IV acute GVHD, grade II-IV and chronic GVHD, reduced nonrelapse mortality (HR = 0.66, p = 0.05), improved leukemia-free survival (HR = 0.74, p = 0.02), overall survival (HR = 0.69, p = 0.01), and GVHD-relapse free survival (HR = 0.62, p < 0.01). In MRD+ patients, ATG was associated with a lower incidence of chronic GVHD (total, HR 0.56 p = 0.03; extensive, HR 0.40 P = 0.01), without an impact on other allo-HCT outcome parameters, including RI(HR = 1.02, p = 0.92). The use of ATG was associated with reduced risk for GVHD. ATG did not increase RI, even in high-risk AML patients who were MRD+ before allo-HCT.

PMID: 31728052 [PubMed - as supplied by publisher]

Common oral diseases in allogeneic haematopoietic stem cell transplantation (HSCT) recipients pre-HSCT.

La, 16/11/2019 - 23:02
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Common oral diseases in allogeneic haematopoietic stem cell transplantation (HSCT) recipients pre-HSCT.

Eur J Haematol. 2019 Apr;102(4):351-356

Authors: Uutela P, Passweg J, Halter J, Weiger R, Waltimo T, Mauramo M

Abstract
OBJECTIVES: The purpose of this study was to compare the prevalence of common oral diseases between allogeneic haematopoietic stem cell transplantation (HSCT) recipients and healthy controls.
MATERIALS AND METHODS: A total of 143 adult allogeneic HSCT recipients who were treated for haematological malignancies between 2008 and 2016 were included in the study. The HSCT recipients were age and sex matched with healthy controls. A dental examination was performed on the HSCT recipients prior to HSCT. Differences in stimulated saliva flow rate (SSFR), decayed, missing and filled teeth (DMFT) index, number of teeth, number of caries lesions, and measures of current or previous periodontitis (radiological attachment loss >3 mm or probing pocket depth ≥4 mm) between HSCT recipients and controls were examined.
RESULTS: Stimulated saliva flow rate, DMFT index and the number of caries lesions were poorer in the HSCT recipients pre-HSCT compared to controls (all P-values <0.05). No statistically significant differences in the measures of current or previous periodontitis were observed.
CONCLUSIONS: Stimulated saliva flow rate was low and caries was common in HSCT recipients prior to HSCT. Efficient preventive strategies are important in order to maintain the oral health of these patients.

PMID: 30632215 [PubMed - indexed for MEDLINE]

Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT.

La, 16/11/2019 - 23:02
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Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT.

J Hematol Oncol. 2018 03 15;11(1):40

Authors: Ruggeri A, Labopin M, Bacigalupo A, Afanasyev B, Cornelissen JJ, Elmaagacli A, Itälä-Remes M, Blaise D, Meijer E, Koc Y, Milpied N, Schouten HC, Kroeger N, Mohty M, Nagler A

Abstract
BACKGROUND: Experience using post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis in allogeneic stem cell transplantation (HSCT) from matched sibling donors (MSD) or unrelated donors (UD) is limited and with controversial results. The study aim was to evaluate PT-Cy as GVHD prophylaxis post-HSCT from MSD and UD transplants. We analyzed 423 patients with acute leukemia who received PT-Cy alone or in combination with other immunosuppressive (IS) drugs as GVHD prophylaxis. Seventy-eight patients received PT-Cy alone (group 1); 204 received PT-Cy in combination with one IS drug-cyclosporine-A (CSA) or methotrexate (MTX) or mycophenolate-mofetil (MMF) (group 2), while 141 patients received PT-Cy in combination with two IS drugs-CSA + MTX or CSA + MMF (group 3). Transplants were performed from 2007 to 2015 and median follow-up was 20 months.
RESULTS: Probability of overall survival (OS) at 2 years was 50, 52.2, and 62.4%, for the three groups, respectively, p = 0.06. In multivariate analysis, in comparison to PT-Cy alone, the addition of two IS drugs was associated with reduced risk of extensive cGVHD (HR 0.25, p = 0.02). Use of bone marrow (BM) and anti-thymocyte globulin were independently associated with reduced risk of extensive cGVHD. Prognostic factors for non-relapse mortality (NRM) were the addition of two IS drugs to PT-Cy (HR 0.35, p = 0.04), diagnosis of AML, disease status at transplant, and patient CMV serology. Factors associated with increased OS were the use of PT-Cy with two IS drugs (HR 0.49, p = 0.02), AML, and disease status at transplant.
CONCLUSION: For GVHD prophylaxis in MSD and UD HSCT, the addition of IS drugs to PT-Cy enhances its effect and reduces the risk of severe cGVHD, reducing mortality and improving survival.

PMID: 29544522 [PubMed - indexed for MEDLINE]

Whole Exome and Transcriptome Sequencing in 1042 Cases Reveals Distinct Clinically Relevant Genetic Subgroups of Follicular Lymphoma.

Pe, 15/11/2019 - 23:02
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Whole Exome and Transcriptome Sequencing in 1042 Cases Reveals Distinct Clinically Relevant Genetic Subgroups of Follicular Lymphoma.

Blood. 2019 Nov 13;134(Supplement_1):19

Authors: Li X, Kositsky R, Reddy A, Love C, Naresh K, Koff JL, Nystrand I, Leppä S, Pasanen A, Karjalainen-Lindsberg ML, Dunkel J, Kovanen P, Qin Q, Bhagat G, Leeman-Neill RJ, Goswami RS, Wildeman S, Delabie J, Burack R, Evans AG, Amador C, Yuan J, Qureishi HN, Li S, Xu J, Yin CC, Gang AO, Norgaard PH, Pedersen MØ, Chan JY, Cheah DMZ, Ong SY, Cheng CL, Lee L, Paulua F, Ondrejka SL, Hsi ED, Czader M, Wang L, Landis A, Churnetski MC, Jaye DL, Flowers CR, McCall CM, Neff J, McKinney MS, Fedoriw Y, Powers E, Montgomery ND, Bogusz AM, Stafford Hintz A, Kovach AE, Reddy N, Thompson Arildsen MA, Mason EF, Juskevicius R, Choi W, Au-Yeung R, Tse E, Sarno V, Chadburn A, Lopez R, Chapman JR, Behdad A, Goldschmidt N, Goodlad J, Burton C, Pillai R, Louissaint A, Soliman DS, Panea R, Dave T, Xiong B, Smith E, Dave S

Abstract
DISCLOSURES: Koff: Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Lymphoma Research Foundation: Research Funding; American Association for Cancer Research: Research Funding. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Gang:ROCHE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Flowers:AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Neff:Enzyvant: Consultancy; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fedoriw:Alexion Pharmaceuticals: Other: Consultant and Speaker. Reddy:Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy; Abbvie: Consultancy. Mason:Sysmex: Honoraria. Behdad:Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Speaker. Burton:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dave:Data Driven Bioscience: Equity Ownership.

PMID: 31723982 [PubMed - in process]

Future directions for therapeutic strategies in post-ischaemic vascularization: a position paper from European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology.

Pe, 15/11/2019 - 23:02
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Future directions for therapeutic strategies in post-ischaemic vascularization: a position paper from European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology.

Cardiovasc Res. 2018 09 01;114(11):1411-1421

Authors: Caporali A, Bäck M, Daemen MJ, Hoefer IE, Jones EA, Lutgens E, Matter CM, Bochaton-Piallat ML, Siekmann AF, Sluimer JC, Steffens S, Tuñón J, Vindis C, Wentzel JJ, Ylä-Herttuala S, Evans PC

Abstract
Modulation of vessel growth holds great promise for treatment of cardiovascular disease. Strategies to promote vascularization can potentially restore function in ischaemic tissues. On the other hand, plaque neovascularization has been shown to associate with vulnerable plaque phenotypes and adverse events. The current lack of clinical success in regulating vascularization illustrates the complexity of the vascularization process, which involves a delicate balance between pro- and anti-angiogenic regulators and effectors. This is compounded by limitations in the models used to study vascularization that do not reflect the eventual clinical target population. Nevertheless, there is a large body of evidence that validate the importance of angiogenesis as a therapeutic concept. The overall aim of this Position Paper of the ESC Working Group of Atherosclerosis and Vascular biology is to provide guidance for the next steps to be taken from pre-clinical studies on vascularization towards clinical application. To this end, the current state of knowledge in terms of therapeutic strategies for targeting vascularization in post-ischaemic disease is reviewed and discussed. A consensus statement is provided on how to optimize vascularization studies for the identification of suitable targets, the use of animal models of disease, and the analysis of novel delivery methods.

PMID: 30016405 [PubMed - indexed for MEDLINE]

Survival after cancer in children, adolescents and young adults in the Nordic countries from 1980 to 2013.

To, 14/11/2019 - 23:02
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Survival after cancer in children, adolescents and young adults in the Nordic countries from 1980 to 2013.

Br J Cancer. 2019 Nov 13;:

Authors: Rostgaard K, Hjalgrim H, Madanat-Harjuoja L, Johannesen TB, Collin S, Hjalgrim LL

Abstract
BACKGROUND: The present study aimed to assess whether the widespread concern of inferior cancer survival in adolescents and young adults (AYAs) compared with children and adults holds true in a Nordic setting with important differences in healthcare organisation compared with the United States (e.g. free access to healthcare) and the United Kingdom (e.g. young teenagers are treated in paediatric departments).
METHODS: Five-year relative survival was calculated for 17 diagnostic groups in patients diagnosed in 2000-2013 in three diagnostic age categories: children (0-14 years), AYAs (15-24 years) and adults (25-34 years).
RESULTS: For 13 out of 17 diagnostic groups examined, there was no difference in survival between AYAs and neighbouring age categories. For acute lymphoblastic leukaemias, astrocytomas, rhabdomyosarcomas and non-rhabdomyosarcoma soft tissue sarcomas we found survival in children to be superior to that in AYAs. For these four diagnostic groups, the rate of survival improvement over three calendar periods (1980-1989, 1990-1999 and 2000-2013) was not particularly low in AYAs compared with neighbouring age categories.
CONCLUSIONS: The present study suggests that in an affluent setting with free access to healthcare, meaningful differences in survival between AYA patients and either childhood or adult patients are a phenomenon of the past for most AYA cancer diagnostic groups.

PMID: 31719686 [PubMed - as supplied by publisher]

Can ELABELA be a novel target in the treatment of chronic lymphocytic leukaemia?

To, 14/11/2019 - 23:02
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Can ELABELA be a novel target in the treatment of chronic lymphocytic leukaemia?

BMC Cancer. 2019 Nov 12;19(1):1086

Authors: Acik DY, Bankir M, Baylan FA, Aygun B

Abstract
BACKGROUND: It has been shown that bcl2, bcl-XL and mcl-1 protein levels are high in chronic lymphocytic leukemia cells, and resultantly, apoptosis does not occur chronic lymphocytic leukemia cells. Apelin and apela (ELABELA/ELA/Toddler) are two peptide ligands for a class A G-protein coupled receptor called apelin receptor. Studies have shown that ELA inhibits apoptosis by inhibiting apoptotic proteins and activating anti-apoptotic proteins. Proteins and genes involved in apoptosis are valuable for targeted cancer therapy. We hypothesized that serum levels may be increased in patients with chronic lymphocytic leukemia based on the antiapoptotic effect of ELA. We compared serum ELABELA levels of healthy volunteers and patients with chronic lymphocytic leukemia. We aimed to draw attention to a new molecule worthy of research in targeted cancer treatment.
METHODS: Forty two untreated CLL patients and 41 healthy volunteers were included in the study. Serum ELA levels were measured by using enzyme-linked immunosorbent assay kits (Dhanghai Sunred Biological Technology co. Ltd), automated ELISA reader (Thermo Scientific, FİNLAND) and computer program (Scanlt for Multiscan F.C.2.5.1) in accordance with the manufacturer's instructions. Statistical analysis was done by Statistical Package for Social Sciences for Windows 20 (IBM SPSS Inc., Chicago, IL) ve MedCalc programs. ELA and variables related to CLL were correlated with Spearman correlation anlysis test. ROC analysis and Youden index method were used to determine a cut off point for ELA. All p-values were 2-sided with statistical significance at 0.05 alpha levels.
RESULTS: In our study, we found that serum ELA levels were significantly higher in patients with CLL.
CONCLUSIONS: This study highlights that ELA targeting may be a potential therapeutic option for treating CLL.

PMID: 31718601 [PubMed - in process]

What could be a cancer mission objective if we join our forces in the fight against cancer?

To, 14/11/2019 - 23:02
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What could be a cancer mission objective if we join our forces in the fight against cancer?

Tumori. 2019 Nov 13;:300891619886351

Authors: Philip T, Karjalainen S, De Lorenzo F, Apostolidis K, Lombardo C, Nilbert M, Lacombe D, Poortmans P, Albreht T, Kearns P, Vassal G

Abstract
The European cancer burden is growing rapidly, with an estimated 2 million deaths a year according to the latest research. As almost half of cancers are diagnosed after the age of 65, and considering the aging European population, a tidal wave of cancer cases will sweep across Europe within the coming decades. Without major action, the additional number of annual cancer cases is expected to rise from 4.2 million to 5.2 million by 2040. If we are to reach plateauing numbers by 2040 (as a minimum goal), this would require 0.75% annual reduction in risk and 1% reduction in risk of death. These challenges call for attack from various angles, coordinated efforts, rational strategies, initiatives throughout the cancer trajectory, activities to reduce inequities, and implementation of evidence-based measures. In order to defeat the societal challenges of cancer through innovation, Europe will need to join forces and connect the European Commission and the member states, politicians and citizens, industries and patient associations. A cancer mission should thus unite the public and patient viewpoint to the perspective of cancer professionals. The authors describe a plan that has been agreed upon among some of the major European Cancer organizations and associations. This plan uses a cancer mission as a tool and must deliver robust medical evidence to patients and doctors through high-quality research delivering sustainable and affordable strategies for prevention, treatment, and follow-up.

PMID: 31718477 [PubMed - as supplied by publisher]

Arpp19 Promotes Myc and Cip2a Expression and Associates with Patient Relapse in Acute Myeloid Leukemia.

To, 14/11/2019 - 23:02
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Arpp19 Promotes Myc and Cip2a Expression and Associates with Patient Relapse in Acute Myeloid Leukemia.

Cancers (Basel). 2019 Nov 11;11(11):

Authors: Mäkelä E, Löyttyniemi E, Salmenniemi U, Kauko O, Varila T, Kairisto V, Itälä-Remes M, Westermarck J

Abstract
Disease relapse from standard chemotherapy in acute myeloid leukemia (AML) is poorly understood. The importance of protein phosphatase 2A (PP2A) as an AML tumor suppressor is emerging. Therefore, here, we examined the potential role of endogenous PP2A inhibitor proteins as biomarkers predicting AML relapse in a standard patient population by using three independent patient materials: cohort1 (n = 80), cohort2 (n = 48) and The Cancer Genome Atlas Acute Myeloid Leukemia (TCGA LAML) dataset (n = 160). Out of the examined PP2A inhibitors (CIP2A, SET, PME1, ARPP19 and TIPRL), expression of ARPP19 mRNA was found to be independent of the current AML risk classification. Functionally, ARPP19 promoted AML cell viability and expression of oncoproteins MYC, CDK1, and CIP2A. Clinically, ARPP19 mRNA expression was significantly lower at diagnosis (p = 0.035) in patients whose disease did not relapse after standard chemotherapy. ARPP19 was an independent predictor for relapse both in univariable (p = 0.007) and in multivariable analyses (p = 0.0001) and gave additive information to EVI1 expression and risk group status (additive effect, p = 0.005). Low ARPP19 expression was also associated with better patient outcome in the TCGA LAML cohort (p = 0.019). In addition, in matched patient samples from diagnosis, remission and relapse phases, ARPP19 expression was associated with disease activity (p = 0.034), indicating its potential usefulness as a minimal residual disease (MRD) marker. Together, these data demonstrate the oncogenic function of ARPP19 in AML and its risk group independent role in predicting AML patient relapse tendency.

PMID: 31717978 [PubMed]

Candidate single nucleotide polymorphisms and thromboembolism in acute lymphoblastic leukemia - A NOPHO ALL2008 study.

Ke, 13/11/2019 - 23:01
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Candidate single nucleotide polymorphisms and thromboembolism in acute lymphoblastic leukemia - A NOPHO ALL2008 study.

Thromb Res. 2019 Nov 07;184:92-98

Authors: Jarvis KB, LeBlanc M, Tulstrup M, Nielsen RL, Albertsen BK, Gupta R, Huttunen P, Jónsson ÓG, Rank CU, Ranta S, Ruud E, Saks K, Trakymiene SS, Tuckuviene R, Schmiegelow K

Abstract
INTRODUCTION: Thromboembolism is a serious toxicity of acute lymphoblastic leukemia treatment, and contributes to substantial morbidity and mortality. Several single nucleotide polymorphisms have been associated with thromboembolism in the general population; however, their impact in patients with acute lymphoblastic leukemia, particularly in children, remains uncertain.
MATERIALS AND METHODS: We collected constitutional DNA and prospectively registered thromboembolic events in 1252 patients, 1-45 years, with acute lymphoblastic leukemia included in the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol in the Nordic and Baltic countries (7/2008-7/2016). Based on previously published data and a priori power calculations, we selected four single nucleotide polymorphisms: F5 rs6025, F11 rs2036914, FGG rs2066865, and ABO rs8176719.
RESULTS: The 2.5 year cumulative incidence of thromboembolism was 7.1% (95% confidence interval (CI) 5.6-8.5). F11 rs2036914 was associated with thromboembolism (hazard ratio (HR) 1.52, 95%CI 1.11-2.07) and there was a borderline significant association for FGG rs2066865 (HR 1.37, 95%CI 0.99-1.91), but no association for ABO rs8176719 or F5 rs6025 in multiple cox regression. A genetic risk score based on F11 rs2036914 and FGG rs2066865 was associated with thromboembolism (HR 1.45 per risk allele, 95%CI 1.15-1.81), the association was strongest in adolescents 10.0-17.9 years (HR 1.64).
CONCLUSION: If validated, a F11 rs2036914/FGG rs2066865 risk prediction model should be tested as a stratification tool for prevention of thromboembolism in patients with acute lymphoblastic leukemia.

PMID: 31715544 [PubMed - as supplied by publisher]

Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization.

Ke, 13/11/2019 - 23:01
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Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization.

Osteoarthritis Cartilage. 2019 Nov 09;:

Authors: Barreto G, Senturk B, Colombo L, Brück O, Neidenbach P, Salzmann G, Zenobi-Wong M, Rottmar M

Abstract
OBJECTIVE: Lumican (LUM) is a major extracellular matrix glycoprotein in adult articular cartilage and its expression is known to be upregulated upon cartilage degeneration. LUM is associated with the pathogen-associated molecular pattern (PAMP) activation of the TLR4 signalling cascade, with TLR4 being highly associated with inflammation in rheumatic diseases. However, the main role of the LUM structural molecule in osteoarthritis (OA) remains elusive. The aim of this study was, therefore, to understand the role of LUM during TLR4-mediated activation in OA.
METHODS: After measuring LUM levels in synovial fluid (SF) of OA patients and lipopolysaccharide (LPS)-induced TLR4 activation, the role of LUM in the expression of pro-inflammatory molecules and cartilage degradation was assessed in vitro and ex vivo in a cartilage explant model. Primary macrophage activation and polarization were studied upon LUM co-stimulation with LPS.
RESULTS: We demonstrate that LUM is not only significantly upregulated in SF from OA patients compared to healthy controls, but also that LUM increases lipopolysaccharide (LPS)-induced TLR4 activation. Furthermore, we show that a pathophysiological level of LUM augments the LPS-induced TLR4 activation and expression of downstream pro-inflammatory molecules, resulting in extensive cartilage degradation. LUM co-stimulation with LPS also provided a pro-inflammatory stimulus, upregulating primary macrophage activation and polarization towards the M1-like phenotype.
CONCLUSIONS: These findings strongly support the role of LUM as a mediator of PAMP-induced TLR4 activation of inflammation, cartilage degradation, and macrophage polarization in the OA joint and potentially other rheumatic diseases.

PMID: 31715293 [PubMed - as supplied by publisher]

Validation and verification of examination procedures in medical laboratories: opinion of the EFLM Working Group Accreditation and ISO/CEN standards (WG-A/ISO) on dealing with ISO 15189:2012 demands for method verification and validation.

Ke, 13/11/2019 - 23:01
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Validation and verification of examination procedures in medical laboratories: opinion of the EFLM Working Group Accreditation and ISO/CEN standards (WG-A/ISO) on dealing with ISO 15189:2012 demands for method verification and validation.

Clin Chem Lab Med. 2019 Nov 12;:

Authors: Roelofsen-de Beer R, Wielders J, Boursier G, Vodnik T, Vanstapel F, Huisman W, Vukasović I, Vaubourdolle M, Sönmez Ç, Linko S, Brugnoni D, Kroupis C, Lohmander M, Šprongl L, Bernabeu-Andreu F, Meško Brguljan P, Thelen M

Abstract
This paper reflects the opinion of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group Accreditation and ISO/CEN standards (WG-A/ISO). It aims to provide guidance for drawing up local/national documents about validation and verification of laboratory methods. We demonstrate how risk evaluation can be used to optimize laboratory policies to meet intended use requirements as well as requirements of standards. This is translated in a number of recommendations on how to introduce risk evaluation in various stages of the implementation of new methods ultimately covering the whole process cycle.

PMID: 31714885 [PubMed - as supplied by publisher]

Twins with different personalities: STAT5B-but not STAT5A-has a key role in BCR/ABL-induced leukemia.

Ke, 13/11/2019 - 23:01
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Twins with different personalities: STAT5B-but not STAT5A-has a key role in BCR/ABL-induced leukemia.

Leukemia. 2019 07;33(7):1583-1597

Authors: Kollmann S, Grundschober E, Maurer B, Warsch W, Grausenburger R, Edlinger L, Huuhtanen J, Lagger S, Hennighausen L, Valent P, Decker T, Strobl B, Mueller M, Mustjoki S, Hoelbl-Kovacic A, Sexl V

Abstract
Deregulation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is found in cancer with STAT5A/B controlling leukemic cell survival and disease progression. As mutations in STAT5B, but not STAT5A, have been frequently described in hematopoietic tumors, we used BCR/ABL as model systems to investigate the contribution of STAT5A or STAT5B for leukemogenesis. The absence of STAT5A decreased cell survival and colony formation. Even more drastic effects were observed in the absence of STAT5B. STAT5B-deficient cells formed BCR/ABL+ colonies or stable cell lines at low frequency. The rarely evolving Stat5b-/- cell lines expressed enhanced levels of BCR/ABL oncoprotein compared to wild-type cells. In line, Stat5b-/- leukemic cells induced leukemia with a significantly prolonged disease onset, whereas Stat5a-/- cells rapidly caused a fatal disease superimposable to wild-type cells. RNA-sequencing (RNA-seq) profiling revealed a marked enhancement of interferon (IFN)-α and IFN-γ signatures in Stat5b-/- cells. Inhibition of IFN responses rescued BCR/ABL+ colony formation of Stat5b-/--deficient cells. A downregulated IFN response was also observed in patients suffering from leukemia carrying STAT5B mutations. Our data define STAT5B as major STAT5 isoform driving BCR/ABL+ leukemia. STAT5B enables transformation by suppressing IFN-α/γ, thereby facilitating leukemogenesis. Our findings might help explain the high frequency of STAT5B mutations in hematopoietic tumors.

PMID: 30679796 [PubMed - indexed for MEDLINE]

Immune cell constitution in bone marrow microenvironment predicts outcome in adult ALL.

Ke, 13/11/2019 - 23:01
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Immune cell constitution in bone marrow microenvironment predicts outcome in adult ALL.

Leukemia. 2019 07;33(7):1570-1582

Authors: Hohtari H, Brück O, Blom S, Turkki R, Sinisalo M, Kovanen PE, Kallioniemi O, Pellinen T, Porkka K, Mustjoki S

Abstract
As novel immunological treatments are gaining a foothold in the treatment of acute lymphoblastic leukemia (ALL), it is elemental to examine ALL immunobiology in more detail. We used multiplexed immunohistochemistry (mIHC) to study the immune contexture in adult precursor B cell ALL bone marrow (BM). In addition, we developed a multivariate risk prediction model that stratified a poor survival group based on clinical parameters and mIHC data. We analyzed BM biopsy samples of ALL patients (n = 52) and healthy controls (n = 14) using mIHC with 30 different immunophenotype markers and computerized image analysis. In ALL BM, the proportions of M1-like macrophages, granzyme B+CD57+CD8+ T cells, and CD27+ T cells were decreased, whereas the proportions of myeloid-derived suppressor cells and M2-like macrophages were increased. Also, the expression of checkpoint molecules PD1 and CTLA4 was elevated. In the multivariate model, age, platelet count, and the proportion of PD1+TIM3+ double-positive CD4+ T cells differentiated a poor survival group. These results were validated by flow cytometry in a separate cohort (n = 31). In conclusion, the immune cell contexture in ALL BM differs from healthy controls. CD4+PD1+TIM3+ T cells were independent predictors of poor outcome in our multivariate risk model, suggesting that PD1 might serve as an attractive immuno-oncological target in B-ALL.

PMID: 30635636 [PubMed - indexed for MEDLINE]

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy.

Ke, 13/11/2019 - 23:01
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Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy.

Cancer Chemother Pharmacol. 2019 01;83(1):53-60

Authors: Nersting J, Nielsen SN, Grell K, Paerregaard M, Abrahamsson J, Lund B, Jonsson OG, Pruunsild K, Vaitkeviciene G, Kanerva J, Schmiegelow K, Nordic Society of Paediatric Haematology and Oncology (NOPHO)

Abstract
PURPOSE: Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing.
METHODS AND RESULTS: Summed MTX with 1-6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58-7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were rs = 0.68 and rs = 0.25-0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all rs ≥ 0.51. MTXpg4 accounted for 29.8 (24.7-33.3)% of MTXpg3-6, yet explained 96% of the summed MTXpg3-6 variation. MTXpg1-4, MTXpg1-6, MTXpg2-6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset.
CONCLUSIONS: Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.

PMID: 30324220 [PubMed - indexed for MEDLINE]

Novel Locally Acting Dual Antiplatelet and Anticoagulant (APAC) Targets Multiple Sites of Vascular Injury in an Experimental Porcine Model.

Ti, 12/11/2019 - 23:01
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Novel Locally Acting Dual Antiplatelet and Anticoagulant (APAC) Targets Multiple Sites of Vascular Injury in an Experimental Porcine Model.

Eur J Vasc Endovasc Surg. 2019 Nov 07;:

Authors: Barreiro KA, Tulamo R, Jouppila A, Albäck A, Lassila R

Abstract
OBJECTIVES: Vascular binding of dual antiplatelet and anticoagulant (APAC) was assessed in surgically created femoral arteriovenous fistula (AVF) and iliac and carotid artery injury in porcine models.
METHODS: Three models of collagen exposing injury were used: 1) femoral AVF, 2) in vivo iliac and carotid artery balloon angioplasty injury, and 3) in vitro femoral artery endothelial denudation injury. Biotinylated APAC (0.5 mg/mL) was incubated with the injury site before releasing blood flow. APAC, von Willebrand factor (vWF), laminin, platelet endothelial cell adhesion molecule 1 (PECAM-1), and podocalyxin were detected in histological sections using immunofluorescence and confocal microscopy and Manders' co-localisation coefficient (M1).
RESULTS: APAC bound to AVF at anastomosis and to both in vivo and in vitro injured arteries. APAC co-localised with matrix vWF (M1 ≥ 0.66) and laminin (M1 ≥ 0.60), but less so if endothelial PECAM-1 or podocalyxin was present (M1 ≤ 0.25). APAC targeted and penetrated the injured vessel wall, especially the AVF vein.
CONCLUSIONS: APAC, compatible with its high negative charge, rapidly targets injured vessels co-localizing with matrix vWF and laminin, but not with endothelial PECAM-1 and podocalyxin. This localising feature may have potential antithrombotic implications for vascular interventions.

PMID: 31708337 [PubMed - as supplied by publisher]

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

La, 09/11/2019 - 23:00
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

NPJ Breast Cancer. 2019;5:38

Authors: Figlioli G, Bogliolo M, Catucci I, Caleca L, Lasheras SV, Pujol R, Kiiski JI, Muranen TA, Barnes DR, Dennis J, Michailidou K, Bolla MK, Leslie G, Aalfs CM, ABCTB Investigators, Adank MA, Adlard J, Agata S, Cadoo K, Agnarsson BA, Ahearn T, Aittomäki K, Ambrosone CB, Andrews L, Anton-Culver H, Antonenkova NN, Arndt V, Arnold N, Aronson KJ, Arun BK, Asseryanis E, Auber B, Auvinen P, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Barwell J, Beane Freeman LE, Beauparlant CJ, Beckmann MW, Behrens S, Benitez J, Berger R, Bermisheva M, Blanco AM, Blomqvist C, Bogdanova NV, Bojesen A, Bojesen SE, Bonanni B, Borg A, Brady AF, Brauch H, Brenner H, Brüning T, Burwinkel B, Buys SS, Caldés T, Caliebe A, Caligo MA, Campa D, Campbell IG, Canzian F, Castelao JE, Chang-Claude J, Chanock SJ, Claes KBM, Clarke CL, Collavoli A, Conner TA, Cox DG, Cybulski C, Czene K, Daly MB, de la Hoya M, Devilee P, Diez O, Ding YC, Dite GS, Ditsch N, Domchek SM, Dorfling CM, Dos-Santos-Silva I, Durda K, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Eriksson M, Evans DG, Fasching PA, Figueroa J, Flyger H, Foulkes WD, Friebel TM, Friedman E, Gabrielson M, Gaddam P, Gago-Dominguez M, Gao C, Gapstur SM, Garber J, García-Closas M, García-Sáenz JA, Gaudet MM, Gayther SA, GEMO Study Collaborators, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, Guénel P, Gutierrez-Barrera AM, Haeberle L, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hein A, Heyworth J, Hillemanns P, Hollestelle A, Hopper JL, Hosgood HD, Howell A, Hu C, Hulick PJ, Hunter DJ, Imyanitov EN, KConFab, Isaacs C, Jakimovska M, Jakubowska A, James P, Janavicius R, Janni W, John EM, Jones ME, Jung A, Kaaks R, Karlan BY, Khusnutdinova E, Kitahara CM, Konstantopoulou I, Koutros S, Kraft P, Lambrechts D, Lazaro C, Le Marchand L, Lester J, Lesueur F, Lilyquist J, Loud JT, Lu KH, Luben RN, Lubinski J, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martens JWM, Maurer T, Mavroudis D, Mebirouk N, Meindl A, Menon U, Miller A, Montagna M, Nathanson KL, Neuhausen SL, Newman WG, Nguyen-Dumont T, Nielsen FC, Nielsen S, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Olshan AF, Olson JE, Olsson H, Osorio A, Ottini L, Peissel B, Peixoto A, Peto J, Plaseska-Karanfilska D, Pocza T, Presneau N, Pujana MA, Punie K, Rack B, Rantala J, Rashid MU, Rau-Murthy R, Rennert G, Lejbkowicz F, Rhenius V, Romero A, Rookus MA, Ross EA, Rossing M, Rudaitis V, Ruebner M, Saloustros E, Sanden K, Santamariña M, Scheuner MT, Schmutzler RK, Schneider M, Scott C, Senter L, Shah M, Sharma P, Shu XO, Simard J, Singer CF, Sohn C, Soucy P, Southey MC, Spinelli JJ, Steele L, Stoppa-Lyonnet D, Tapper WJ, Teixeira MR, Terry MB, Thomassen M, Thompson J, Thull DL, Tischkowitz M, Tollenaar RAEM, Torres D, Troester MA, Truong T, Tung N, Untch M, Vachon CM, van Rensburg EJ, van Veen EM, Vega A, Viel A, Wappenschmidt B, Weitzel JN, Wendt C, Wieme G, Wolk A, Yang XR, Zheng W, Ziogas A, Zorn KK, Dunning AM, Lush M, Wang Q, McGuffog L, Parsons MT, Pharoah PDP, Fostira F, Toland AE, Andrulis IL, Ramus SJ, Swerdlow AJ, Greene MH, Chung WK, Milne RL, Chenevix-Trench G, Dörk T, Schmidt MK, Easton DF, Radice P, Hahnen E, Antoniou AC, Couch FJ, Nevanlinna H, Surrallés J, Peterlongo P

Abstract
Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

PMID: 31700994 [PubMed]

HLA-selected platelets for platelet refractory patients with HLA antibodies: a single-center experience.

La, 09/11/2019 - 23:00
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HLA-selected platelets for platelet refractory patients with HLA antibodies: a single-center experience.

Transfusion. 2019 03;59(3):945-952

Authors: Karlström C, Linjama T, Edgren G, Lauronen J, Wikman A, Höglund P

Abstract
BACKGROUND: Platelet refractoriness due to HLA immunization represents a problem in transfusion management of thrombocytopenic hematology patients. Refractory patients can be managed by HLA-selected platelet transfusions, but the optimal matching strategy is debated and how the degree of HLA mismatch influences transfusion outcome is poorly studied.
STUDY DESIGN AND METHODS: We studied 32 hematology patients who received 142 matched platelet units between 2007 and 2016. Four matching strategies were compared: 1) genomic HLA typing at the two digit level, performed using polymerase chain reaction-sequence-specific oligonucleotide probing; 2) serologic "eplet score" calculated using HLAMatchmaker; 3) cross-matching using lymphocyte cytotoxicity; and 4) matching based on donor-specific antibody (DSA) specificity, determined using Luminex. A 1-hour corrected count increment (CCI) of more than 7.5 × 109 /L was considered a successful response.
RESULTS: Selection of platelets with either a complete HLA match or an acceptable HLA mismatch based on genomic typing and DSA information, each predicted 86% successful transfusion responses. For HLA-mismatched transfusions, the eplet score correlated with CCI and the fraction of successful transfusions, but less well compared to DSA matching. Cytotoxic crossmatching was least predictive. For transfusions across one to four DSAs, the antibody reaction strength correlated with the 1-hour CCI, but many transfusions were successful despite the presence of DSA.
CONCLUSION: A complete HLA-A and -B match or an acceptable mismatch based on DSA should guide identification of donors. Still, transfusions across DSAs are often successful, emphasizing that the presence of DSA is necessary but not sufficient for platelet clearance.

PMID: 30575964 [PubMed - indexed for MEDLINE]

Cost-effectiveness analysis of PSA-based mass screening: Evidence from a randomised controlled trial combined with register data.

To, 07/11/2019 - 23:00
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Cost-effectiveness analysis of PSA-based mass screening: Evidence from a randomised controlled trial combined with register data.

PLoS One. 2019;14(11):e0224479

Authors: Booth N, Rissanen P, Tammela TLJ, Kujala P, Stenman UH, Taari K, Talala K, Auvinen A

Abstract
In contrast to earlier studies which have used modelling to perform cost-effectiveness analysis, this study links data from a randomised controlled trial with register data from nationwide registries to reveal new evidence on costs, effectiveness, and cost-effectiveness of organised mass prostate-cancer screening based on prostate-specific antigen (PSA) testing. Cost-effectiveness analyses were conducted with individual-level data on health-care costs from comprehensive registers and register data on real-world effectiveness from the two arms of the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC), following 80,149 men from 1996 through 2015. The study examines cost-effectiveness in terms of overall mortality and, in addition, in terms of diagnosed men's mortality from prostate cancer and mortality with but not from prostate cancer. Neither arm of the FinRSPC was clearly more cost-effective in analysis in terms of overall mortality. Organised screening in the FinRSPC could be considered cost-effective in terms of deaths from prostate cancer: averting just over one death per 1000 men screened. However, even with an estimated incremental cost-effectiveness ratio of below 20,000€ per death avoided, this result should not be considered in isolation. This is because mass screening in this trial also resulted in increases in death with, but not from, prostate cancer: with over five additional deaths per 1000 men screened. Analysis of real-world data from the FinRSPC reveals new evidence of the comparative effectiveness of PSA-based screening after 20 years of follow-up, suggesting the possibility of higher mortality, as well as higher healthcare costs, for screening-arm men who have been diagnosed with prostate cancer but who do not die from it. These findings should be corroborated or contradicted by similar analyses using data from other trials, in order to reveal if more diagnosed men have also died in the screening arms of other trials of mass screening for prostate cancer.

PMID: 31689326 [PubMed - in process]

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

Ti, 05/11/2019 - 22:59
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Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

Am J Hum Genet. 2019 01 03;104(1):21-34

Authors: Mavaddat N, Michailidou K, Dennis J, Lush M, Fachal L, Lee A, Tyrer JP, Chen TH, Wang Q, Bolla MK, Yang X, Adank MA, Ahearn T, Aittomäki K, Allen J, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Auer PL, Auvinen P, Barrdahl M, Beane Freeman LE, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bernstein L, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Børresen-Dale AL, Brauch H, Bremer M, Brenner H, Brentnall A, Brock IW, Brooks-Wilson A, Brucker SY, Brüning T, Burwinkel B, Campa D, Carter BD, Castelao JE, Chanock SJ, Chlebowski R, Christiansen H, Clarke CL, Collée JM, Cordina-Duverger E, Cornelissen S, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dos-Santos-Silva I, Dumont M, Durcan L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Engel C, Eriksson M, Evans DG, Fasching PA, Figueroa J, Fletcher O, Flyger H, Försti A, Fritschi L, Gabrielson M, Gago-Dominguez M, Gapstur SM, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Gilyazova IR, Glendon G, Goldberg MS, Goldgar DE, González-Neira A, Grenaker Alnæs GI, Grip M, Gronwald J, Grundy A, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hankinson SE, Harkness EF, Hart SN, He W, Hein A, Heyworth J, Hillemanns P, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Howell A, Huang G, Humphreys K, Hunter DJ, Jakimovska M, Jakubowska A, Janni W, John EM, Johnson N, Jones ME, Jukkola-Vuorinen A, Jung A, Kaaks R, Kaczmarek K, Kataja V, Keeman R, Kerin MJ, Khusnutdinova E, Kiiski JI, Knight JA, Ko YD, Kosma VM, Koutros S, Kristensen VN, Krüger U, Kühl T, Lambrechts D, Le Marchand L, Lee E, Lejbkowicz F, Lilyquist J, Lindblom A, Lindström S, Lissowska J, Lo WY, Loibl S, Long J, Lubiński J, Lux MP, MacInnis RJ, Maishman T, Makalic E, Maleva Kostovska I, Mannermaa A, Manoukian S, Margolin S, Martens JWM, Martinez ME, Mavroudis D, McLean C, Meindl A, Menon U, Middha P, Miller N, Moreno F, Mulligan AM, Mulot C, Muñoz-Garzon VM, Neuhausen SL, Nevanlinna H, Neven P, Newman WG, Nielsen SF, Nordestgaard BG, Norman A, Offit K, Olson JE, Olsson H, Orr N, Pankratz VS, Park-Simon TW, Perez JIA, Pérez-Barrios C, Peterlongo P, Peto J, Pinchev M, Plaseska-Karanfilska D, Polley EC, Prentice R, Presneau N, Prokofyeva D, Purrington K, Pylkäs K, Rack B, Radice P, Rau-Murthy R, Rennert G, Rennert HS, Rhenius V, Robson M, Romero A, Ruddy KJ, Ruebner M, Saloustros E, Sandler DP, Sawyer EJ, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schumacher F, Schürmann P, Schwentner L, Scott C, Scott RJ, Seynaeve C, Shah M, Sherman ME, Shrubsole MJ, Shu XO, Slager S, Smeets A, Sohn C, Soucy P, Southey MC, Spinelli JJ, Stegmaier C, Stone J, Swerdlow AJ, Tamimi RM, Tapper WJ, Taylor JA, Terry MB, Thöne K, Tollenaar RAEM, Tomlinson I, Truong T, Tzardi M, Ulmer HU, Untch M, Vachon CM, van Veen EM, Vijai J, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett W, Winqvist R, Wolk A, Yang XR, Yannoukakos D, Zhang Y, Zheng W, Ziogas A, ABCTB Investigators, kConFab/AOCS Investigators, NBCS Collaborators, Dunning AM, Thompson DJ, Chenevix-Trench G, Chang-Claude J, Schmidt MK, Hall P, Milne RL, Pharoah PDP, Antoniou AC, Chatterjee N, Kraft P, García-Closas M, Simard J, Easton DF

Abstract
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

PMID: 30554720 [PubMed - indexed for MEDLINE]