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  • 1. Bergmann, Troels K.
    et al.
    Brasch-Andersen, Charlotte
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mirza, Mansoor R.
    Skougaard, Kristin
    Wihl, Jessica
    Keldsen, Nina
    Damkier, Per
    Peterson, Curt
    Vach, Werner
    Brosen, Kim
    Impact of ABCB1 Variants on Neutrophil Depression: A Pharmacogenomic Study of Paclitaxel in 92 Women with Ovarian Cancer2012Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 110, nr 2, s. 199-204Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The standard treatment for ovarian cancer in advanced stages is post-surgery treatment with taxane-platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose-limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter-individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p-value 0.03). A similar association was found for G2677T /A, p-value 0.02. For C1236T, there was a trend with p-value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy.

  • 2. Bergmann, Troels K.
    et al.
    Vach, Werner
    Feddersen, Soren
    Eckhoff, Lise
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Herrstedt, Jörn
    Brosen, Kim
    GWAS-based association between RWDD3 and TECTA variants and paclitaxel induced neuropathy could not be confirmed in Scandinavian ovarian cancer patients2013Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, nr 4, s. 871-873Artikkel i tidsskrift (Fagfellevurdert)
  • 3.
    Bjorn, Niclas
    et al.
    Linköping Univ, Div Drug Res, Dept Biomed & Clin Sci, Clin Pharmacol, Linköping, Sweden..
    Badam, Tejaswi Venkata Satya
    Linköping Univ, Dept Phys Chem & Biol, Bioinformat, Linköping, Sweden.;Univ Skövde, Sch Biosci, Syst Biol Res Ctr, Skövde, Sweden..
    Spalinskas, Rapolas
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Branden, Eva
    Gävle Cent Hosp, Dept Resp Med, Gävle, Sweden.;Uppsala Univ Reg Gävleborg, Ctr Res & Dev, Gävle, Sweden..
    Koyi, Hirsh
    Gävle Cent Hosp, Dept Resp Med, Gävle, Sweden.;Uppsala Univ Reg Gävleborg, Ctr Res & Dev, Gävle, Sweden..
    Lewensohn, Rolf
    Karolinska Univ Hosp, Thorac Oncol Unit, Tema Canc, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    De Petris, Luigi
    Karolinska Univ Hosp, Thorac Oncol Unit, Tema Canc, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Lubovac-Pilav, Zelmina
    Univ Skövde, Sch Biosci, Syst Biol Res Ctr, Skövde, Sweden..
    Sahlén, Pelin
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Lundeberg, Joakim
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Gustafsson, Mika
    Linköping Univ, Dept Phys Chem & Biol, Bioinformat, Linköping, Sweden..
    Gréen, Henrik
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Linköping Univ, Div Drug Res, Dept Biomed & Clin Sci, Clin Pharmacol, Linköping, Sweden.; Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linköping, Sweden..
    Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients2020Inngår i: NPJ SYSTEMS BIOLOGY AND APPLICATIONS, ISSN 2056-7189, Vol. 6, nr 1, artikkel-id 25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gemcitabine/carboplatin chemotherapy commonly induces myelosuppression, including neutropenia, leukopenia, and thrombocytopenia. Predicting patients at risk of these adverse drug reactions (ADRs) and adjusting treatments accordingly is a long-term goal of personalized medicine. This study used whole-genome sequencing (WGS) of blood samples from 96 gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients and gene network modules for predicting myelosuppression. Association of genetic variants in PLINK found 4594, 5019, and 5066 autosomal SNVs/INDELs withp <= 1 x 10(-3)for neutropenia, leukopenia, and thrombocytopenia, respectively. Based on the SNVs/INDELs we identified the toxicity module, consisting of 215 unique overlapping genes inferred from MCODE-generated gene network modules of 350, 345, and 313 genes, respectively. These module genes showed enrichment for differentially expressed genes in rat bone marrow, human bone marrow, and human cell lines exposed to carboplatin and gemcitabine (p < 0.05). Then using 80% of the patients as training data, random LASSO reduced the number of SNVs/INDELs in the toxicity module into a feasible prediction model consisting of 62 SNVs/INDELs that accurately predict both the training and the test (remaining 20%) data with high (CTCAE 3-4) and low (CTCAE 0-1) maximal myelosuppressive toxicity completely, with the receiver-operating characteristic (ROC) area under the curve (AUC) of 100%. The present study shows how WGS, gene network modules, and random LASSO can be used to develop a feasible and tested model for predicting myelosuppressive toxicity. Although the proposed model predicts myelosuppression in this study, further evaluation in other studies is required to determine its reproducibility, usability, and clinical effect.

  • 4. Björn, N.
    et al.
    Sigurgeirsson, Benjamin
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
    Svedberg, A.
    Pradhananga, Sailendra
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Brandén, E.
    Koyi, H.
    Lewensohn, R.
    de Petris, L.
    Apellániz-Ruiz, M.
    Rodríguez-Antona, C.
    Lundeberg, Joakim
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Gréen, Henrik
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia2020Inngår i: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 20, nr 2, s. 179-191Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.

  • 5. Christensen, Mette M. H.
    et al.
    Brasch-Andersen, Charlotte
    Green, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Division of Drug Research, Department of Medicine and Health Sciences, Clinical Pharmacology, Faculty of Health Sciences, Linköping University, Linköpingg.
    Nielsen, Flemming
    Damkier, Per
    Beck-Nielsen, Henning
    Brosen, Kim
    The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c2011Inngår i: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 21, nr 12, s. 837-850Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective The aim of this study was to evaluate the effect of genetic variations in OCT1, OCT2, MATE1, MATE 2, and PMAT on the trough steady-state plasma concentration of metformin and hemoglobin A1c (Hb1Ac). Method The South Danish Diabetes Study was a 2 x 2 x 2 factorial, prospective, randomized, double-blind, placebo-controlled, multicentre study. One hundred and fifty-nine patients received 1 g of metformin, twice daily continuously, and 415 repeated plasma metformin measurements were obtained after 3, 6, and 9 months of treatment.

    Results The mean trough steady-state metformin plasma concentration was estimated to be 576 ng/ml (range, 54-4133 ng/ml, rho = 0.55) and correlated to the number of reduced function alleles in OCT1 (none, one or two: 642, 542, 397 ng/ml; P = 0.001). The absolute decrease in Hb1Ac both initially and long term was also correlated to the number of reduced function alleles in OCT1 resulting in diminished pharmacodynamic effect of metformin after 6 and 24 months.

    Conclusion In a large cohort of type 2 diabetics, we either confirm or show for the first time: (a) an enormous 80-fold) variability in trough steady-state metformin plasma concentration, (b) OCT1 activity affects metformin steady-state pharmacokinetics, and (c) OCT1 genotype has a bearing on HbA1c during metformin treatment.

  • 6. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjorn
    Nahi, Hareth
    Hermanson, Monica
    Rosenquist, Richard
    Hoglund, Martin
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lotfi, Kourosh
    Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype2014Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 167, nr 5, s. 671-680Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Drug resistance is a clinically relevant problem in the treatment of acute myeloid leukaemia (AML). We have previously reported a relationship between single nucleotide polymorphisms (SNPs) of ABCB1, encoding the multi-drug transporter P-glycoprotein, and overall survival (OS) in normal karyotype (NK)-AML. Here we extended this material, enabling subgroup analysis based on FLT3 and NPM1 status, to further elucidate the influence of ABCB1 SNPs. De novo NK-AML patients (n = 201) were analysed for 1199G>A, 1236C>T, 2677G>T/A and 3435C>T, and correlations to outcome were investigated. FLT3 wild-type 1236C/C patients have significantly shorter OS compared to patients carrying the variant allele; medians 20 vs. 49 months, respectively, P = 0.017. There was also an inferior outcome in FLT3 wild-type 2677G/G patients compared to patients carrying the variant allele, median OS 20 vs. 35 months, respectively, P = 0.039. This was confirmed in Cox regression analysis. Our results indicate that ABCB1 1236C>T and 2677G>T may be used as prognostic markers to distinguish relatively high risk patients in the intermediate risk FLT3 wild-type group, which may contribute to future individualizing of treatment strategies.

  • 7. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjörn
    Nahi, Hareth
    Hermanson, Monica
    Rosenquist, Richard
    Höglund, Martin
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lotfi, Kourosh
    Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5 '-nucleotidase2013Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, nr 12, s. 1001-1006Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A> C rs2072671 and 2451C> T rs532545), 50-nucleotidase (cN-II 7A> G rs10883841), and deoxycytidine kinase (DCK 30UTR 948T> C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and 2451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P< 0.001 and 5 vs. 23 months, P50.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P50.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML.

  • 8. Fransson, Martin N.
    et al.
    Brugård, Jan
    Aronsson, Peter
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Semi-physiologically based pharmacokinetic modeling of paclitaxel metabolism and in silico-based study of the dynamic sensitivities in pathway kinetics2012Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 47, nr 4, s. 759-767Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To build a semi-physiologically based pharmacokinetic model describing the uptake, metabolism and efflux of paclitaxel and its metabolites and investigate the effect of hypothetical genetic polymorphisms causing reduced uptake, metabolism or efflux in the pathway by model simulation and sensitivity analysis. Methods: A previously described intracellular pharmacokinetic model was used as a starting point for model development. Kinetics for metabolism, transport, binding and systemic and output compartments were added to mimic a physiological model with hepatic elimination. Model parameters were calibrated using constraints postulated as ratios of concentrations and amounts of metabolites and drug in the systemic plasma and output compartments. The sensitivity in kinetic parameters was tested using dynamic sensitivity analysis. Results: Predicted plasma concentrations of drug and metabolites were in the range of what has been observed in clinical studies. Given the final model, plasma concentrations of paclitaxel seems to be relatively little affected by changes in metabolism or transport, while its main metabolite may be largely affected even by small changes. If metabolites prove to be clinically relevant, genetic polymorphisms may play an important role for individualizing paclitaxel treatment.

  • 9. Green, Anna
    et al.
    Green, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Linkoping University, Sweden.
    Rehnberg, Malin
    Svensson, Anneli
    Gunnarsson, Cecilia
    Jonasson, Jon
    Assessment of HaloPlex Amplification for Sequence Capture and Massively Parallel Sequencing of Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes2015Inngår i: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, nr 1, s. 31-42Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is complex. Mutations in genes encoding components of the cardiac desmosomes have been implicated as being causally related to ARVC. Next-generation sequencing allows parallel sequencing and duplication/deletion analysis of many genes simultaneously, which is appropriate for screening of mutations in disorders with heterogeneous genetic backgrounds. We designed and validated a next-generation sequencing test panel for ARVC using HaloPlex. We used SureDesign to prepare a HaloPlex enrichment system for sequencing of DES, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43, and TIN from patients with ARVC using a MiSeq instrument. Performance characteristics were determined by comparison with Sanger, as the gold standard, and TruSeq Custom Amplicon sequencing of DSC2, DSG2, DSP, JUP, and PKP2. All the samples were successfully sequenced after HaloPlex capture, with >99% of targeted nucleotides covered by >20x. The sequences were of high quality, although one problematic area due to a presumptive context-specific sequencing error causing motif Located in exon 1 of the DSP gene was detected. The mutations found by Sanger sequencing were also found using the HaloPlex technique. Depending on the bioinformatics pipeline, sensitivity varied from 99.3% to 100%, and specificity varied from 99.90/0 to 100%. Three variant positions found by Sanger and HaloPlex sequencing were missed by TruSeq Custom Amplicon owing to Loss of coverage.

  • 10.
    Green, Henrik
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Khan, Muhammad Suleman
    Jakobsen-Falk, Ingrid
    Avall-Lundqvist, Elisabeth
    Peterson, Curt
    Impact of CYP3A5(*)3 and CYP2C8-HapC on Paclitaxel/Carboplatin-Induced Myelosuppression in Patients with Ovarian Cancer2011Inngår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, nr 10, s. 4205-4209Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The influence of genetic variants on paclitaxel-induced toxicity is of considerable interest for reducing adverse drug reactions. Recently, the genetic variants CYP2C8(*)3, CYP2C8-HapC, and CYP3A5(*)3 were associated with paclitaxel-induced neurotoxicity. We, therefore, investigated the impact of CYP2C8-HapC and CYP3A5(*)3 on paclitaxel/carboplatin-induced myelosuppression and neurotoxicity. Thirty-three patients from a prospective pharmacokinetics study were genotyped using pyrosequencing. Patients with variant alleles of CYP2C8-HapC were found to have significantly lower nadir values of both leukocytes and neutrophils (p < 0.05) than patients with the wild-type genotype. CYP3A5(*)3/(*)1 patients were shown to have borderline, significantly lower nadir values of leukocytes (p = 0.07) than (*)3/(*)3 patients. Combining the two genotypes resulted in a significant correlation with both leukopenia and neutropenia (p = 0.01). No effect of these genetic variants on neurotoxicity could be shown in this rather small study, but their importance for paclitaxel-induced toxicity could be confirmed.

  • 11.
    Green, Henrik
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Stål, O.
    Bachmeier, K.
    Bäcklund, L. M.
    Carlsson, L.
    Hansen, J.
    Lagerlund, M.
    Norberg, B.
    Franzén, Å.
    Åleskog, A.
    Malmström, A.
    Pegylated liposomal doxorubicin as first-line monotherapy in elderly women with locally advanced or metastatic breast cancer: Novel treatment predictive factors identified2011Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 313, nr 2, s. 145-153Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We investigated the efficacy and safety of single-agent pegylated liposomal doxorubicin (PLD) as first-line treatment for elderly women with advanced breast cancer and evaluated predictive markers for response and toxicity. Twenty-five women >= 65 years received 40 mg/m(2) PLD every 28 days. Time to treatment failure (TTF), response rate, time to progression (TTP) and overall survival (OS) was calculated. The ABCB1 single nucleotide polymorphisms (SNP), tumor MRN complex, and TOPOII alpha were analyzed. A mean of 7.4 cycles PLD were administered and TIT was 5.5 months and OS 20.6 months. ABCB1 SNPs were found to correlate to both efficacy and toxicity, while tumor expression of the MRN complex and TOPOII alpha correlated to TTP. PLD is a safe and effective treatment for elderly breast cancer patients. Also potential predictive markers were identified.

  • 12.
    Hasmats, Johanna
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Orear, Cedric
    Validire, Pierre
    Huss, Mikael
    Käller, Max
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Assessment of Whole Genome Amplification for Sequence Capture and Massively Parallel Sequencing2014Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 9, nr 1, s. e84785-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Exome sequence capture and massively parallel sequencing can be combined to achieve inexpensive and rapid global analyses of the functional sections of the genome. The difficulties of working with relatively small quantities of genetic material, as may be necessary when sharing tumor biopsies between collaborators for instance, can be overcome using whole genome amplification. However, the potential drawbacks of using a whole genome amplification technology based on random primers in combination with sequence capture followed by massively parallel sequencing have not yet been examined in detail, especially in the context of mutation discovery in tumor material. In this work, we compare mutations detected in sequence data for unamplified DNA, whole genome amplified DNA, and RNA originating from the same tumor tissue samples from 16 patients diagnosed with non-small cell lung cancer. The results obtained provide a comprehensive overview of the merits of these techniques for mutation analysis. We evaluated the identified genetic variants, and found that most (74%) of them were observed in both the amplified and the unamplified sequence data. Eighty-nine percent of the variations found by WGA were shared with unamplified DNA. We demonstrate a strategy for avoiding allelic bias by including RNA-sequencing information.

  • 13.
    Hasmats, Johanna
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Solnestam, Beata Werne
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zajac, Pawel
    Huss, Mikael
    Orear, Cedric
    Validire, Pierre
    Bjursell, Magnus
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Validation of whole genome amplification for analysis of the p53 tumor suppressor gene in limited amounts of tumor samples2012Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 425, nr 2, s. 379-383Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Personalized cancer treatment requires molecular characterization of individual tumor biopsies. These samples are frequently only available in limited quantities hampering genomic analysis. Several whole genome amplification (WGA) protocols have been developed with reported varying representation of genomic regions post amplification. In this study we investigate region dropout using a 929 polymerase based WGA approach. DNA from 123 lung cancers specimens and corresponding normal tissue were used and evaluated by Sanger sequencing of the p53 exons 5-8. To enable comparative analysis of this scarce material, WGA samples were compared with unamplified material using a pooling strategy of the 123 samples. In addition, a more detailed analysis of exon 7 amplicons were performed followed by extensive cloning and Sanger sequencing. Interestingly, by comparing data from the pooled samples to the individually sequenced exon 7, we demonstrate that mutations are more easily recovered from WGA pools and this was also supported by simulations of different sequencing coverage. Overall this data indicate a limited random loss of genomic regions supporting the use of whole genome amplification for genomic analysis.

  • 14.
    Hasmats, Johanna
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kupershmidt, Ilya
    Edsgärd, Daniel
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    de Petris, Luigi
    Lewensohn, Rolf
    Alexeyenko, Andrey
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Blackhall, Fiona
    Bess, Benjamin
    Lindgren, Andrea
    Sörenson, Sverre
    Brandén, Eva
    Koyi, Hirsh
    Peterson, Curt
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Using whole exome sequencing to identify genetic candidates for carboplatin and gemcitabine induced toxicitiesArtikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Chemotherapies are associated with significant inter-individual variability in therapeutic effect and adverse drug reactions. In lung cancer the use of gemcitabine and carboplatin induces grade 3-4 myelosuppression in about ¼ of the patients while an equal fraction of patients are basically unaffected in terms of myelosuppressive side effects. We therefore set out to try to identify genetic markers for gemcitabine / carboplatin induced myelosuppression. We selected 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0-1 after the first chemotherapy cycle) by the chemotherapy out of 243 lung cancer patients treated with gemcitabine / carboplatin. These patients were exome sequenced and their genetic differences compared using six different bioinformatic strategies; whole exome non-synonymous SNV association analysis, deviation from Hardy-Weinberg equilibrium, analysis of genes selected by a priori biological knowledge, analysis of genes selected from gene expression meta-analysis of toxicity data sets, Ingenuity pathway analysis and FunCoup network enrichment analysis. All patients were successfully sequenced and 5000-7000 non-synonymous single nucleotide variants were identified in each patient. PI3 (elastase specific inhibitor in neutrophils) showed the strongest association in the single SNV analysis (nominal p=0.0005). Further, variants within IL37, an inhibitor of the innate immune system, and CSAG1, a tumor antigen, differed among the two patient groups and appeared among the top hits in several of the performed analysis, indicating that the approach identifies genetic variants associated with the immune system and tumor differentiation, which might be important for the sensitivity to chemotherapeutic agents. However, the associations reported here are in a need of replication before clinical interpretations can be made.

  • 15.
    Hasmats, Johanna
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kupershmidt, Ilya
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Rodriguez-Antona, Cristina
    Su, Qiaojuan Jane
    Khan, Muhammad Suleman
    Jara, Carlos
    Mielgo, Xabier
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Identification of candidate SNPs for drug induced toxicity from differentially expressed genes in associated tissues2012Inngår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 506, nr 1, s. 62-68Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The growing collection of publicly available high-throughput data provides an invaluable resource for generating preliminary in silico data in support of novel hypotheses. In this study we used a cross-dataset meta-analysis strategy to identify novel candidate genes and genetic variations relevant to paclitaxel/carboplatin-induced myelosuppression and neuropathy. We identified genes affected by drug exposure and present in tissues associated with toxicity. From ten top-ranked genes 42 non-synonymous single nucleotide polymorphisms (SNPs) were identified in silico and genotyped in 94 cancer patients treated with carboplatin/paclitaxel. We observed variations in 11 SNPs, of which seven were present in a sufficient frequency for statistical evaluation. Of these seven SNPs. three were present in ABCA1 and ATM, and showed significant or borderline significant association with either myelosuppression or neuropathy. The strikingly high number of associations between genotype and clinically observed toxicity provides support for our data-driven computations strategy to identify biomarkers for drug toxicity.

  • 16. Karlsson, L.
    et al.
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zackrisson, A. L.
    Bengtsson, F.
    Jakobsen Falk, I.
    Carlsson, B.
    Ahlner, J.
    Kugelberg, F. C.
    ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram2013Inngår i: International journal of legal medicine, ISSN 0937-9827, E-ISSN 1437-1596, Vol. 127, nr 3, s. 579-586Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter at the blood-brain barrier. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates like citalopram and venlafaxine. In this study, we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases involving these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The study included 228 forensic autopsy cases with different causes and manners of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined. The SNPs C1236T and C3435T in venlafaxine-positive cases were significantly different between the intoxication cases and non-intoxications. This was not seen for cases involving citalopram, indicating that the effect of genetic variants might be substrate specific. This novel finding should, however, be confirmed in future studies with larger number of cases.

  • 17. Khan, Muhammad Suleman
    et al.
    Zetterlund, Eva-Lena
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Linköping University, Sweden.
    Oscarsson, Anna
    Zackrisson, Anna-Lena
    Svanborg, Eva
    Lindholm, Maj-Lis
    Persson, Harald
    Eintrei, Christina
    Pharmacogenetics, Plasma Concentrations, Clinical Signs and EEG During Propofol Treatment2014Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, nr 6, s. 565-570Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A variety of techniques have been developed to monitor the depth of anaesthesia. Propofol's pharmacokinetics and response vary greatly, which might be explained by genetic polymorphisms. We investigated the impact of genetic variations on dosage, anaesthetic depth and recovery after total intravenous anaesthesia with propofol. A total of 101 patients were enrolled in the study. The plasma concentration of propofol during anaesthesia was measured using high-performance liquid chromatography. EEG was monitored during the surgical procedure as a measure of anaesthetic depth. Pyrosequencing was used to determine genetic polymorphisms in CYP2B6, CYP2C9, the UGTIA9-promotor and the GABRE gene. The correlation between genotype and to plasma concentration at the time of loss of consciousness (LOC), the total induction dose, the time to anaesthesia, eye opening and clearance were investigated. EEG monitoring showed that the majority of the patients had not reached a sufficient level of anaesthetic depth (subdelta) at the time of loss of consciousness despite a high induction dose of propofol. Patients with UGT1A9-331C/T had a higher propofol clearance than those without (p=0.03) and required a higher induction dose (p=0.03). The patients with UGT1A9-1818T/C required a longer time to LOC (p=0.03). The patients with CYP2C9*2 had a higher concentration of propofol at the time of LOC (p=0.02). The polymorphisms in the metabolizing enzymes and the receptor could not explain the large variation seen in the pharmacokinetics of propofol and the clinical response seen. At LOC, the patients showed a large difference in EEG pattern.

  • 18. Leandro-Garcia, Luis J.
    et al.
    Inglada-Perez, Lucia
    Pita, Guillermo
    Hjerpe, Elisabet
    Leskelae, Susanna
    Jara, Carlos
    Mielgo, Xabier
    Gonzalez-Neira, Anna
    Robledo, Mercedes
    Avall-Lundqvist, Elisabeth
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Rodriguez-Antona, Cristina
    Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy2013Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 50, nr 9, s. 599-605Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. Methods A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. Results The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0x10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4x10(-5) and rs1159057, p=6.8x10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4x10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1x10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0x10(-7)). Conclusions This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.

  • 19. Leandro-Garcia, Luis J.
    et al.
    Leskelä, Susanna
    Jara, Carlos
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Åvall-Lundqvist, Elisabeth
    Wheeler, Heather E.
    Dolan, M. Eileen
    Inglada-Perez, Lucia
    Maliszewska, Agnieszka
    de Cubas, Aguirre A.
    Comino-Mendez, Inaki
    Mancikova, Veronika
    Cascon, Alberto
    Robledo, Mercedes
    Rodriguez-Antona, Cristina
    Regulatory Polymorphisms in beta-Tubulin IIa Are Associated with Paclitaxel-Induced Peripheral Neuropathy2012Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, nr 16, s. 4441-4448Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated through beta-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in beta-tubulin genes. Experimental Design: We measured variation in gene expression of three beta-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel-induced cytotoxicity in lymphoblastoid cell lines was compared with beta-tubulin expression as measured by Affymetrix exon array. Results: We found a 63-fold variation in beta-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at -101, -112, and -157 in TUBB2A promoter correlated with increased mRNA levels. The -101 and -112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42-0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity. Conclusions: This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a beta-tubulin gene.

  • 20. Ljungberg, Liza U.
    et al.
    Persson, Karin
    Eriksson, Andreas C.
    Green, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Whiss, Per A.
    Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro2013Inngår i: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, nr 2, s. 932-938Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cigarette smoking is a leading cause of cardiovascular disease. The cardiovascular effects of smoking are probably multifactorial, including effects on platelets. Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent. The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets. None of the metabolites cotinine, cotinine-N-oxide, nicotine-1'-N-oxide or trans-3'-hydroxycotinine (0.1-10 mu M) affected platelet aggregation or P-selectin expression. Nicotine (10 mu M) weakly increased platelet aggregation, whereas trans-3'-hydroxycotinine (0.1 mu M) and nicotine-1'-N-oxide (1-10 mu M) weakly inhibited adhesion to fibrinogen. To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function. Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently. The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor. Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge. As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff.

  • 21. Moreno, Samuel Boiso
    et al.
    Zackrisson, Anna-Lena
    Falk, Ingrid Jakobsen
    Karlsson, Louise
    Carlsson, Björn
    Tillmar, Andreas
    Kugelberg, Fredrik C.
    Ahlner, Johan
    Hägg, Staffan
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    ABCB1 gene polymorphisms are associated with suicide in forensic autopsies2013Inngår i: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 23, nr 9, s. 463-469Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics.Objective The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199G>A, 1236C>T, 2677G>T/A, and 3435C>T in deaths by suicide.Patients and methods A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases.Results There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases.Conclusion Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.

  • 22. Rodríguez-Antona, C.
    et al.
    Gréen, Henrik
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Linköping Univ, Fac Hlth Sci, Div Drug Res, Linköping, Sweden.
    Microtubule-targeting drugs and personalization of cancer treatment2011Inngår i: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 12, nr 4, s. 449-451Artikkel i tidsskrift (Annet vitenskapelig)
  • 23. Sivik, T.
    et al.
    Vikingsson, S.
    Gréen, Henrik
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Jansson, A.
    Expression patterns of 17β-hydroxysteroid dehydrogenase 14 in human tissues2012Inngår i: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 44, nr 13, s. 949-956Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    17βHSD enzymes catalyze the stereospecific oxidation/reduction at carbon 17β of androgens and estrogens, and are important players in intracrine sex hormone synthesis. The biological relevance of 17βHSD14, first named retSDR3, is largely unknown. We generated and validated an antibody targeting the 17βHSD14 antigen and used this for immunohistochemical evaluation of expression patterns in 33 healthy human tissues. Furthermore, sex steroid conversional activity in HSD17B14 overexpressing HEK293 and MCF10A cells was investigated by assessing interconversion products of estrone, estradiol, androstenedione, testosterone, and dehydroepiandrosterone. Immunohistochemical staining patterns of 17βHSD14 with the enzyme being primarily expressed in glandular epithelial tissue reveal an enzyme with possible implications in the secretion or conversion of externally derived compounds. A role for 17βHSD14 in sex steroid metabolism is supported by the finding that 17HSD14 oxidizes both estradiol and testosterone into less bioactive steroid metabolites estrone and androstenedione, respectively.

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