Identification of genomic regions contributing to etoposide-induced cytotoxicity

Wasim K. Bleibel, Shiwei Duan, Stephanie R. Huang, Emily O. Kistner, Sunita J. Shukla, Xiaolin Wu, Judith A. Badner, Eileen M. Dolan

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Etoposide is routinely used in combination-based chemotherapy for testicular cancer and small-cell lung cancer; however, myelosuppression, therapy-related leukemia and neurotoxicity limit its utility. To determine the genetic contribution to cellular sensitivity to etoposide, we evaluated cell growth inhibition in Centre d'Etude du Polymorphisme Humain lymphoblastoid cell lines from 24 multi-generational pedigrees (321 samples) following treatment with 0.02-2.5 μM etoposide for 72 h. Heritability analysis showed that genetic variation contributes significantly to the cytotoxic phenotypes (h2 = 0.17-0.25, P = 4.9 × 10-5 -7.3 × 10-3). Whole genome linkage scans uncovered 8 regions with peak LOD scores ranging from 1.57 to 2.55, with the most significant signals being found on chromosome 5 (LOD = 2.55) and chromosome 6 (LOD = 2.52). Linkage-directed association was performed on a subset of HapMap samples within the pedigrees to find 22 SNPs significantly associated with etoposide cytotoxicity at one or more treatment concentrations. UVRAG, a DNA repair gene, SEMA5A, SLC7A6 and PRMT7 are implicated from these unbiased studies. Our findings suggest that susceptibility to etoposide-induced cytotoxicity is heritable and using an integrated genomics approach we identified both genomic regions and SNPs associated with the cytotoxic phenotypes.

Original languageEnglish (US)
Pages (from-to)173-180
Number of pages8
JournalHuman Genetics
Volume125
Issue number2
DOIs
StatePublished - 2009

Bibliographical note

Funding Information:
Acknowledgments We are extremely grateful to Dr. Jeong-Ah Kang for maintaining the cell lines. This Pharmacogenetics of Anticancer Agents Research (PAAR) Group (http://pharmacogenetics.org) study was supported by NIH/NIGMS grant GM61393 with data deposits supported by U01GM61374. Phenotypic data reported in this article can be accessed through http://www.PharmGKB.org by using data accession number PS207137.

Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.

Fingerprint Dive into the research topics of 'Identification of genomic regions contributing to etoposide-induced cytotoxicity'. Together they form a unique fingerprint.

Cite this