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Association studies of exome sequencing data of lung cancer patients undergoing gemcitabine/carboplatin chemotherapy with myelosupression toxicity
KTH, School of Biotechnology (BIO).
2015 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Chemotherapeutic drugs such as carboplatin/gemcitabine administered 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 myekosuppression 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-transforemd (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 transforemd 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. However, variants with p-value <1.00x 10-3 in each studydesign 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 rs 8018462 in SLC7A7 genes were identified by Gene-based SKATO test for TPK and LPK phenotypes. This results could implicated 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 study.

Place, publisher, year, edition, pages
Keyword [en]
Exome squencing, Lung cancer, Myelosupression, Thrombocytopenia, Leukopenia, Neutropenia
National Category
Engineering and Technology
URN: urn:nbn:se:kth:diva-175341OAI: diva2:860338
Available from: 2015-10-13 Created: 2015-10-12 Last updated: 2015-10-13Bibliographically approved

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