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Identification of candidate SNPs for drug induced toxicity from differentially expressed genes in associated tissues
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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2012 (English)In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 506, no 1, 62-68 p.Article in journal (Refereed) Published
Abstract [en]

The growing collection of publicly available high-throughput data provides an invaluable resource for generating preliminary in silico data in support of novel hypotheses. In this study we used a cross-dataset meta-analysis strategy to identify novel candidate genes and genetic variations relevant to paclitaxel/carboplatin-induced myelosuppression and neuropathy. We identified genes affected by drug exposure and present in tissues associated with toxicity. From ten top-ranked genes 42 non-synonymous single nucleotide polymorphisms (SNPs) were identified in silico and genotyped in 94 cancer patients treated with carboplatin/paclitaxel. We observed variations in 11 SNPs, of which seven were present in a sufficient frequency for statistical evaluation. Of these seven SNPs. three were present in ABCA1 and ATM, and showed significant or borderline significant association with either myelosuppression or neuropathy. The strikingly high number of associations between genotype and clinically observed toxicity provides support for our data-driven computations strategy to identify biomarkers for drug toxicity.

Place, publisher, year, edition, pages
2012. Vol. 506, no 1, 62-68 p.
Keyword [en]
Paclitaxel, Carboplatin, Single nucleotide polymorphism, Toxicity, Gene expression microarrays, Meta-analysis
National Category
Genetics
Identifiers
URN: urn:nbn:se:kth:diva-103126DOI: 10.1016/j.gene.2012.06.053ISI: 000308260400010Scopus ID: 2-s2.0-84864511649OAI: oai:DiVA.org:kth-103126DiVA: diva2:559132
Funder
EU, European Research Council, CHEMORES LSHC-CT-2007-037665Swedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20121008

Available from: 2012-10-08 Created: 2012-10-04 Last updated: 2017-12-07Bibliographically 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.
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2012:18
Keyword
Cancer, Mutations, Variations, Single Nucleotide Polymorphism, DNA, RNA, Genome, Massively Parallel Sequencing, Exome Sequencing, Toxicity
National Category
Other Medical Biotechnology
Identifiers
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)
Opponent
Supervisors
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20121105

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

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Hasmats, JohannaKupershmidt, IlyaLundeberg, JoakimGréen, Henrik
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