Association studies of exome sequencing data of lung cancer patients undergoing gemcitabine/carboplatin chemotherapy with myelosuppression toxicity

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Journal ISSN

Volume Title

Perustieteiden korkeakoulu | Master's thesis

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, Joakim

Thesis advisor

Sigurgeirsson, Benjamin

Keywords

exome sequencing, lung cancer, myelosuppression, thrombocytopenia, Leukopenia, neutropenia

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