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Pharmacogenetic biomarkers for chemotherapy-induced adverse drug reactions
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
2019 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2019. , s. 74
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1700
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-162138DOI: 10.3384/diss.diva-162138ISBN: 9789176850046 (tryckt)OAI: oai:DiVA.org:liu-162138DiVA, id: diva2:1371554
Disputas
2019-12-20, Hasselquistsalen, Campus US, Linköping, 09:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2019-11-20 Laget: 2019-11-20 Sist oppdatert: 2020-05-25bibliografisk kontrollert
Delarbeid
1. ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients
Åpne denne publikasjonen i ny fane eller vindu >>ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients
2018 (engelsk)Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, nr 3, s. 277-287Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199Gamp;gt;A (rs2229109), 1236Camp;gt;T (rs1128503), 2677Gamp;gt;T/A (rs2032582), 3435Camp;gt;T (rs1045642) in ABCB1, and 1196Aamp;gt;G (rs10509681) in CYP2C8 and their association with treatment-induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n=260) or Taxol((R)) (Arm B, n=265) were included and genotyped using pyrosequencing. Genotype associations with myelosuppression, PFS and OS were investigated using anova, Kaplan-Meier analysis and Cox proportional hazard models. The most prominent finding was for the ABCB1 variant 3435TT, which was significantly associated with increased PFS in All (hazard ratio (HR) = 0.623), in Arm A (HR=0.590) and in Arm B (HR=0.627), as well as increased OS in All (HR=0.443) and in Arm A (HR=0.372) compared to the wild-type, 3435CC. For toxicity, the most interesting finding concerned the haplotype, including 1236TT, 2677TT and 3435TT, which was associated with higher neutrophil values in Arm B (p=0.039) and less neutrophil decrease in All (p=0.048) and in Arm B (p=0.021). It is noteworthy that the results varied depending on the treatment arm which indicates that the effects of ABCB1 variants vary with the treatment regimen. Our results reflect the contradictory results of previous studies, confirming that small variations in the composition of treatment regimens and patient populations may influence the interpretation of SNPs effects on treatment outcome.

sted, utgiver, år, opplag, sider
WILEY, 2018
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-150852 (URN)10.1111/bcpt.12997 (DOI)000441237300009 ()29504705 (PubMedID)
Merknad

Funding Agencies|Swedish Cancer Society; Swedish Research Council; Linkoping University; ALF grants Region Ostergotland; Oasmia Pharmaceuticals AB, Uppsala, Sweden

Tilgjengelig fra: 2018-09-06 Laget: 2018-09-06 Sist oppdatert: 2019-11-20
2. Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
Åpne denne publikasjonen i ny fane eller vindu >>Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
Vise andre…
2020 (engelsk)Inngår i: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 20, nr 2, s. 179-191Artikkel i tidsskrift (Fagfellevurdert) Published
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.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2020
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-162137 (URN)10.1038/s41397-019-0099-8 (DOI)000521728100003 ()
Merknad

Funding agencies:  Swedish Cancer SocietySwedish Cancer Society; Swedish Research CouncilSwedish Research Council; ALF grants Region ostergotland; Radiumhemmet; Marcus Borgstroms stiftelse; Spanish Ministry of Economy and Competitiveness [SAF2015-64850-R]; Science for Life 

Tilgjengelig fra: 2019-11-20 Laget: 2019-11-20 Sist oppdatert: 2020-04-10bibliografisk kontrollert
3. Comparison of Variant Calls from Whole Genome and Whole Exome Sequencing Data Using Matched Samples
Åpne denne publikasjonen i ny fane eller vindu >>Comparison of Variant Calls from Whole Genome and Whole Exome Sequencing Data Using Matched Samples
Vise andre…
2018 (engelsk)Inngår i: Journal of Next Generation Sequencing & Applications, ISSN 2469-9853, Vol. 5, nr 1, s. 1-8Artikkel i tidsskrift (Fagfellevurdert) 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.

Emneord
Whole genome sequencing; Whole exome sequencing; Coverage; Depth; Genotyping quality; Discordant; Concordant; Variant calls; Single-nucleotide variants
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-155840 (URN)
Merknad

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

Tilgjengelig fra: 2019-03-28 Laget: 2019-03-28 Sist oppdatert: 2019-11-20bibliografisk kontrollert
4. Single-Cell RNA Sequencing of Hematopoietic Stem and Progenitor Cells Treated with Gemcitabine and Carboplatin.
Åpne denne publikasjonen i ny fane eller vindu >>Single-Cell RNA Sequencing of Hematopoietic Stem and Progenitor Cells Treated with Gemcitabine and Carboplatin.
2020 (engelsk)Inngår i: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 11, nr 5, artikkel-id E549Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Treatments that include gemcitabine and carboplatin induce dose-limiting myelosuppression. The understanding of how human bone marrow is affected on a transcriptional level leading to the development of myelosuppression is required for the implementation of personalized treatments in the future. In this study, we treated human hematopoietic stem and progenitor cells (HSPCs) harvested from a patient with chronic myelogenous leukemia (CML) with gemcitabine/carboplatin. Thereafter, scRNA-seq was performed to distinguish transcriptional effects induced by gemcitabine/carboplatin. Gene expression was calculated and evaluated among cells within and between samples compared to untreated cells. Cell cycle analysis showed that the treatments effectively decrease cell proliferation, indicated by the proportion of cells in the G2M-phase dropping from 35% in untreated cells to 14.3% in treated cells. Clustering and t-SNE showed that cells within samples and between treated and untreated samples were affected differently. Enrichment analysis of differentially expressed genes showed that the treatments influence KEGG pathways and Gene Ontologies related to myeloid cell proliferation/differentiation, immune response, cancer, and the cell cycle. The present study shows the feasibility of using scRNA-seq and chemotherapy-treated HSPCs to find genes, pathways, and biological processes affected among and between treated and untreated cells. This indicates the possible gains of using single-cell toxicity studies for personalized medicine.

Emneord
adverse drug reactions, carboplatin, gemcitabine, hematopoietic stem and progenitor cells, myelosuppression, single-cell RNA sequencing, toxicity
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-165784 (URN)10.3390/genes11050549 (DOI)32422951 (PubMedID)
Tilgjengelig fra: 2020-05-25 Laget: 2020-05-25 Sist oppdatert: 2020-05-25

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