Identification of genomic regions contributing to etoposide-induced cytotoxicity.
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 microM etoposide for 72 h. Heritability analysis showed that genetic variation contributes significantly to the cytotoxic phenotypes (h (2) = 0.17-0.25, P = 4.9 x 10(-5)-7.3 x 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.
Bleibel
Wasim K
WK
Department of Medicine, University of Chicago, 5841 S. Maryland Ave, Box MC2115, Chicago, IL 60637, USA.
Duan
Shiwei
S
Huang
R Stephanie
RS
Kistner
Emily O
EO
Shukla
Sunita J
SJ
Wu
Xiaolin
X
Badner
Judith A
JA
Dolan
M Eileen
ME
D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology*; D008040:Genetic Linkage; D014644:Genetic Variation; D023281:Genomics / Q000379:methods*; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D008126:Lod Score; D008565:Membrane Proteins / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D010597:Pharmacogenetics; D011484:Protein-Arginine N-Methyltransferases; D039961:Semaphorins; D025521:Tumor Suppressor Proteins / Q000235:genetics
D026923:Amino Acid Transport Systems, Basic; D000972:Antineoplastic Agents, Phytogenic; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C491228:SEMA5A protein, human; C469951:SLC7A6 protein, human; D039961:Semaphorins; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human; D005047:Etoposide; D008780:Methyltransferases; C487994:PRMT7 protein, human; D011484:Protein-Arginine N-Methyltransferases