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Using whole exome sequencing to identify genetic candidates for carboplatin and gemcitabine induced toxicities
KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
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(English)Article in journal (Other academic) Submitted
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.

Keyword [en]
Exome sequencing, Gemcitabine, Carboplatin, Thrombocytopenia, Neutropenia, Toxicity
National Category
URN: urn:nbn:se:kth:diva-104474OAI: diva2:564871

QS 2012

Available from: 2012-11-05 Created: 2012-11-05 Last updated: 2012-11-05Bibliographically approved
In thesis
1. Analysis of genetic variations in cancer
Open this publication in new window or tab >>Analysis of genetic variations in cancer
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis is to apply recently developed technologies for genomic variation analyses, and to ensure quality of the generated information for use in preclinical cancer research.

Faster access to a patients’ full genomic sequence for a lower cost makes it possible for end users such as clinicians and physicians to gain a more complete understanding of the disease status of a patient and adjust treatment accordingly. Correct biological interpretation is important in this context, and can only be provided through fast and simple access to relevant high quality data.

Therefore, we here propose and validate new bioinformatic strategies for biomarker selection for prediction of response to cancer therapy. We initially explored the use of bioinformatic tools to select interesting targets for toxicity in carboplatin and paclitaxel on a smaller scale. From our findings we then further extended the analysis to the entire exome to look for biomarkers as targets for adverse effects from carboplatin and gemcitabine. To investigate any bias introduced by the methods used for targeting the exome, we analyzed the mutation profiles in cancer patients by comparing whole genome amplified DNA to unamplified DNA. In addition, we applied RNA-seq to the same patients to further validate the variations obtained by sequencing of DNA. The understanding of the human cancer genome is growing rapidly, thanks to methodological development of analysis tools. The next step is to implement these tools as a part of a chain from diagnosis of patients to genomic research to personalized treatment.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. iii, 62 p.
TRITA-BIO-Report, ISSN 1654-2312 ; 2012:18
Cancer, Mutations, Variations, Single Nucleotide Polymorphism, DNA, RNA, Genome, Massively Parallel Sequencing, Exome Sequencing, Toxicity
National Category
Other Medical Biotechnology
urn:nbn:se:kth:diva-104438 (URN)978-91-7501-450-0 (ISBN)
Public defence
2012-11-22, Hillarpsalen, Retzius väg 8, Karolinska Institutet, Solna, 09:00 (English)
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience

QC 20121105

Available from: 2012-11-05 Created: 2012-11-02 Last updated: 2014-02-11Bibliographically approved

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Hasmats, JohannaKupershmidt, IlyaEdsgärd, DanielLundeberg, JoakimGréen, Henrik
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