Association studies of exome sequencing data of lung cancer patients undergoing gemcitabine/carboplatin chemotherapy with myelosuppression toxicity
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Journal Title
Journal ISSN
Volume Title
Perustieteiden korkeakoulu |
Master's thesis
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Author
Date
2015-08-27
Department
Major/Subject
Computational Systems Biology
Mcode
IL3013
Degree programme
Master's Degree Programme in Computational and Systems Biology (euSYSBIO)
Language
en
Pages
74+8
Series
Abstract
Chemotherapeutic drugs such as carboplatin/gemcitabine administerd to non small cell lung cancer (NSCLC) patients frequently induce myelosuppression toxicity potentially leading to reduction or removal of drugs. We set out to identify the genetic variants associated with toxicity induced myelosuppression by whole exome sequencing (WES) 216 NSCLC patients and associating biallelic variants with different quantitative and qualitative measurements of myelosuppression phenotypes. WES identified on average 29834 variants in each patient. Biallelic variants from combined patients genotype were associated with each myelosupression phenotype - Thrombocytopenia (TPK), Leukopenia (LPK) and Neutropenia (NPK) using quantitative Log-transformed (LN) and Empirical normal quantile transformation (ENQT) phenotypes and qualitative high/low toxicity study design in linear and logistic regression methods. Additionally, gene-based SKATO tests were performed for transformed quantitative phenotypes to investigate enrichment of rare and common variants. Due to sample size limitation, none of the variants reached multiple corrected Bonferroni significant or FDR-BH p - values <1.00 X 10-3 . However, variants with p-value in each study design were evaluated for high toxicity. We found five, one and two variants for TPK, LPK and NPK respectively associated in all quantitative and qualitative single variant association study. Furthermore, single variant rs4808 in CAPZA2 and rs8018462 in SLC7A7 genes were identified by Gene-based SKATO test for TPK and LPK phenotypes. This results could implicate association of CAPZA2 and SLC7A7 to TPK and LPK myleosupression. However, validation and replication of the variants and genes needs to be further studied in an independent studies.Description
Supervisor
Lundeberg, JoakimThesis advisor
Sigurgeirsson, BenjaminKeywords
exome sequencing, lung cancer, myelosuppression, thrombocytopenia, Leukopenia, neutropenia
