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Comparison of Variant Calls from Whole Genome and Whole Exome Sequencing Data Using Matched Samples
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden; School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
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2018 (English)In: Journal of Next Generation Sequencing & Applications, ISSN 2469-9853, Vol. 5, no 1, p. 1-8Article in journal (Refereed) Published
Abstract [en]

Whole exome sequencing (WES) has been extensively used in genomic research. As sequencing costs decline it is being replaced by whole genome sequencing (WGS) in large-scale genomic studies, but more comparative information on WES and WGS datasets would be valuable. Thus, we have extensively compared variant calls obtained from WGS and WES of matched germline DNA samples from 96 lung cancer patients. WGS provided more homogeneous coverage with higher genotyping quality, and identified more variants, than WES, regardless of exome coverage depth. It also called more reference variants, reflecting its power to call rare variants, and more heterozygous variants that met applied quality criteria, indicating that WGS is less prone to allelic drop outs. However, increasing WES coverage reduced the discrepancy between the WES and WGS results. We believe that as sequencing costs further decline WGS will become the method of choice even for research confined to the exome.

Place, publisher, year, edition, pages
2018. Vol. 5, no 1, p. 1-8
Keywords [en]
Whole genome sequencing; Whole exome sequencing; Coverage; Depth; Genotyping quality; Discordant; Concordant; Variant calls; Single-nucleotide variants
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:liu:diva-155840OAI: oai:DiVA.org:liu-155840DiVA, id: diva2:1300159
Note

DOI not working/activated: https://doi.org/10.4172/2469-9853.1000154

Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-11-20Bibliographically approved
In thesis
1. Pharmacogenetic biomarkers for chemotherapy-induced adverse drug reactions
Open this publication in new window or tab >>Pharmacogenetic biomarkers for chemotherapy-induced adverse drug reactions
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer is a serious disease expected to be the world-leading cause of death in the 21st century. The use of harsh chemotherapies is motivated and accepted but, unfortunately, is often accompanied by severe toxicity and adverse drug reactions (ADRs). These occur because the classical chemotherapies’ common modes of action effectively kill and/or reduce the growth rate not only of tumour cells, but also of many other rapidly dividing healthy cells in the body. There are also considerable interindividual differences in ADRs, even between patients with similar cancers and disease stage treated with equal doses; some experience severe to life-threatening ADRs after one dose, leading to treatment delays, adjustments, or even discontinuation resulting in suboptimal treatment, while others remain unaffected through all treatment cycles. Being able to predict which patients are at high or low risk of ADRs, and to adjust doses accordingly before treatment, would probably decrease toxicity and patient suffering while also increasing treatment tolerability and effects. In this thesis, we have used next-generation sequencing (NGS) and bioinformatics for the prediction of myelosuppressive ADRs in lung and ovarian cancer patients treated with gemcitabine/carboplatin and paclitaxel/carboplatin.

Paper I shows that ABCB1 and CYP2C8 genotypes have small effects inadequate for stratification of paclitaxel/carboplatin toxicity. This supports the transition to whole-exome sequencing (WES) and whole-genome sequencing (WGS). Papers II and IV, respectively, use WES and WGS, and demonstrate that genetic variation in or around genes involved in blood cell regulation and proliferation, or genes differentially expressed at chemotherapy exposure, can be used in polygenic prediction models for stratification of gemcitabine/carboplatininduced myelosuppression. Paper III reassuringly shows that WES and WGS are concordant and mostly yield comparable genotypes across the exome. Paper V proves that single-cell RNA sequencing of hematopoietic stem cells is a feasible method for elucidating differential transcriptional effects induced as a response to in vitro chemotherapy treatment.

In conclusion, our results supports the transition to genome-wide approaches using WES, WGS, and RNA sequencing to establish polygenic models that combine effects of multiple pharmacogenetic biomarkers for predicting chemotherapy-induced ADRs. This approach could be applied to improve risk stratification and our understanding of toxicity and ADRs related to other drugs and diseases. We hope that our myelosuppression prediction models can be refined and validated to facilitate personalized treatments, leading to increased patient wellbeing and quality of life.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. p. 74
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1700
National Category
Cancer and Oncology Pharmacology and Toxicology Medicinal Chemistry Medical Genetics
Identifiers
urn:nbn:se:liu:diva-162138 (URN)10.3384/diss.diva-162138 (DOI)9789176850046 (ISBN)
Public defence
2019-12-20, Hasselquistsalen, Campus US, Linköping, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2020-02-06Bibliographically approved

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Björn, NiclasGreen, Henrik

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