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Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients
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- Björn, Niclas, 1990- (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Linköping Univ, Div Drug Res, Dept Biomed & Clin Sci, Clin Pharmacol, Linköping, Sweden.,Clinical Pharmacology, Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Sweden
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- Badam, Tejaswi Venkata Satya, 1989- (author)
- Högskolan i Skövde,Linköpings universitet,Bioinformatik,Tekniska fakulteten,School of Bioscience, Systems Biology Research Centre, University of Skövde,Linköping Univ, Dept Phys Chem & Biol, Bioinformat, Linköping, Sweden.;Univ Skövde, Sch Biosci, Syst Biol Res Ctr, Skövde, Sweden.,Institutionen för biovetenskap,Forskningsmiljön Systembiologi,Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Sweden,Translationell Bioinformatik, Translational Bioinformatics
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- Spalinskas, Rapolas, Dr. 1983- (author)
- KTH,Science for Life Laboratory, SciLifeLab,Genteknologi,Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden,KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Gene Technol, Sci Life Lab, Solna, Sweden.
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- 2020-08-24
- 2020
- English.
- In: npj Systems Biology and Applications. - : Nature Publishing Group. - 2056-7189. ; 6:1
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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 with p ≤ 1 × 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- NATURVETENSKAP -- Biologi -- Bioinformatik och systembiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Bioinformatics and Systems Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
Keyword
- Cancer
- Genetic interaction
- Systems analysis
- Bioinformatik
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- ref (subject category)
- art (subject category)
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