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Genetic association of gemcitabine/carboplatin induced myelosuppression in patients with non-small cell lung cancer using whole exome sequencing
KTH, School of Biotechnology (BIO), Gene Technology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Purpose: Chemotherapy induced myelosuppression is a recurrent problem in cancer treatment, both for the patients’ quality of life and response. Severe hematological toxicities lead to dose reduction, postponed or ceased treatment, affecting the treatment effect. Identifying genetic markers associated with toxicity is an important factor for individualized chemotherapy and might increase the overall effect of the treatment.

Material and methods: Non-small cell lung cancer patients undergoing gemcitabine/carboplatin chemotherapy were included and their exomes were sequenced. Genetic variants from 212 exomes were correlated to thrombocytopenia, leukopenia, and neutropenia on single nucleotide and gene level. Results were processed through enrichment analysis and variants were validated using externally available datasets.

Results: SNV analysis identified 103, 131 and 112 variants to be associated with thrombocytopenia, leukopenia and neutropenia, respectively. Gene based analysis identified 21, 54 and 31 genes to be associated with thrombocytopenia, leukopenia and neutropenia, respectively. Using external data sets 8, 26 and 9 SNVs were validated through linkage disequilibrium for thrombocytopenia, leukopenia and neutropenia, respectively.

The variant rs61739531 (CADD = 25.7) in the gene MYO1G was identified to be associated with high toxicity in all forms of myelosuppression. Validated variants include rs6118 (CADD = 22.3) in SERPINA5, rs16910526 (CADD = 35.0) in CLEC7A and rs79350244 (CADD = 24.2) in DNAH2. Enrichment analysis of associated genes identified the pathways hemostasis, HIF-1 alpha transcription factor network and vitamin B12 metabolism to be involved in thrombocytopenia, leukopenia and neutropenia, respectively.

Factors involved in megakaryocyte development and platelet production, was also associated with thrombocytopenia for three genes JMJD1C with the variant rs34491125 (CADD = 22.1), DOCK8 with the variant rs10491684 (CADD = 11.7) and CAPZA2 based on three variants in the gene based analysis.

Conclusion: The results highlight genetic markers and relevant pathways associated with chemotherapy induced myelosuppression and form a strong foundation for further investigation into toxicity induced myelosuppression. 

Keyword [en]
chemotherapy, adverse drug reaction, exome sequencing, lung cancer, myelosuppression
National Category
Cancer and Oncology
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-184155OAI: oai:DiVA.org:kth-184155DiVA: diva2:915137
Funder
Swedish Cancer SocietySwedish Research Council
Note

QC 20160404

Available from: 2016-03-29 Created: 2016-03-29 Last updated: 2016-04-04Bibliographically approved
In thesis
1. Analysis of RNA and DNA sequencing data: Improved bioinformatics applications
Open this publication in new window or tab >>Analysis of RNA and DNA sequencing data: Improved bioinformatics applications
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Massively parallel sequencing has rapidly revolutionized DNA and RNA research. Sample preparations are steadfastly advancing, sequencing costs have plummeted and throughput is ever growing. This progress has resulted in exponential growth in data generation with a corresponding demand for bioinformatic solutions. This thesis addresses methodological aspects of this sequencing revolution and applies it to selected biological topics.

Papers I and II are technical in nature and concern sample preparation and data anal- ysis of RNA sequencing data. Paper I is focused on RNA degradation and paper II on generating strand specific RNA-seq libraries.

Paper III and IV deal with current biological issues. In paper III, whole exomes of cancer patients undergoing chemotherapy are sequenced and their genetic variants associ- ated to their toxicity induced adverse drug reactions. In paper IV a comprehensive view of the gene expression of the endometrium is assessed from two time points of the menstrual cycle.

Together these papers show relevant aspects of contemporary sequencing technologies and how it can be applied to diverse biological topics. 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2016. 135 p.
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2016:2
Keyword
RNA sequencing, exome sequencing, bioinformatics, gene expression, differential expression, variant calling
National Category
Bioinformatics and Systems Biology
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-184158 (URN)978-91-7595-894-1 (ISBN)
Public defence
2016-04-22, Inghesalen, Tomtebodavägen 18A, Solna, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

QC 20160329

Available from: 2016-03-29 Created: 2016-03-29 Last updated: 2016-03-29Bibliographically approved

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