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Genes and variants ...
Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
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- Björn, Niclas (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Linkoping Univ, Dept Med & Hlth Sci, Div Drug Res, Clin Pharmacol, Linkoping, Sweden
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- Sigurgeirsson, Benjamin (author)
- KTH,Genteknologi,Science for Life Laboratory, SciLifeLab,Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden; School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland
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- Svedberg, Anna, 1988- (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Linkoping Univ, Dept Med & Hlth Sci, Div Drug Res, Clin Pharmacol, Linkoping, Sweden
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- Pradhananga, Sailendra (author)
- KTH,Genteknologi,Science for Life Laboratory, SciLifeLab,Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden
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- Brandén, Eva (author)
- Uppsala universitet,Centrum för klinisk forskning, Gävleborg,Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden,Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden
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- Koyi, Hirsh (author)
- Karolinska Institutet,Uppsala universitet,Centrum för klinisk forskning, Gävleborg,Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden,Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden
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- Lewensohn, Rolf (author)
- Karolinska Institutet,Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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- de Petris, Luigi (author)
- Karolinska Institutet,Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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- Apellániz-Ruiz, Maria (author)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain,Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Madrid, Spain
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- Rodríguez-Antona, Cristina (author)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain,Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Madrid, Spain
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- Lundeberg, Joakim (author)
- KTH,Science for Life Laboratory, SciLifeLab,Genteknologi,Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden
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- Gréen, Henrik, 1975- (author)
- KTH,Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Linkoping Univ, Dept Med & Hlth Sci, Div Drug Res, Clin Pharmacol, Linkoping, Sweden;KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Div Gene Technol, Sci Life Lab, Solna, Sweden;Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden,Genteknologi,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
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(creator_code:org_t)
- 2019-10-15
- 2020
- English.
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In: The Pharmacogenomics Journal. - : Nature Publishing Group. - 1470-269X .- 1473-1150. ; 20:2, s. 179-191
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- TEKNIK OCH TEKNOLOGIER -- Industriell bioteknik -- Medicinsk bioteknik (hsv//swe)
- ENGINEERING AND TECHNOLOGY -- Industrial Biotechnology -- Medical Biotechnology (hsv//eng)
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Björn, Niclas
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Sigurgeirsson, B ...
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Svedberg, Anna, ...
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Pradhananga, Sai ...
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Brandén, Eva
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Koyi, Hirsh
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Lewensohn, Rolf
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de Petris, Luigi
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Apellániz-Ruiz, ...
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Rodríguez-Antona ...
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Lundeberg, Joaki ...
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Gréen, Henrik, 1 ...
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The Pharmacogeno ...
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Linköping University
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Uppsala University
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Royal Institute of Technology
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Karolinska Institutet