Comprehensive evaluation of the contribution of X chromosome genes to platinum sensitivity.
Using a genome-wide gene expression data set generated from Affymetrix GeneChip Human Exon 1.0ST array, we comprehensively surveyed the role of 322 X chromosome gene expression traits on cellular sensitivity to cisplatin and carboplatin. We identified 31 and 17 X chromosome genes whose expression levels are significantly correlated (after multiple testing correction) with sensitivity to carboplatin and cisplatin, respectively, in the combined HapMap CEU (Utah residents with ancestry from northern and western Europe) and YRI (Yoruba in Ibahan, Nigeria) populations (false discovery rate, FDR < 0.05). Of those, 14 overlap for both cisplatin and carboplatin. Using an independent gene expression quantification method, the Illumina Sentrix Human-6 Expression BeadChip, measured on the same HapMap cell lines, we found that 4 and 2 of these genes are significantly associated with carboplatin and cisplatin sensitivity, respectively, in both analyses. Two genes, CTPS2 and DLG3, were identified by both genome-wide gene expression analyses as correlated with cellular sensitivity to both platinating agents. The expression of DLG3 gene was also found to correlate with cellular sensitivity to platinating agents in NCI-60 cancer cell lines. In addition, we evaluated whether the expression of X chromosome genes contributed to the observed differences in sensitivity to the platinums between CEU and YRI-derived cell lines. Of the 34 distinct genes significantly correlated with either carboplatin or cisplatin sensitivity, 14 are differentially expressed (defined as P < 0.05) between CEU and YRI. Thus, sex chromosome genes play a role in cellular sensitivity to platinating agents and differences in the expression level of these genes are an important source of variation that should be included in comprehensive pharmacogenomic studies.
Section of Genetic Medicine, Department of Medicine, The University of Chicago, 900 E. 57 street, KCBD room 7148, Chicago, IL 60637, USA.
Eric R
ER
Gamazon
Hae Kyung
HK
Im
Peter H
PH
O'Donnell
Dana
D
Ziliak
Amy L
AL
Stark
Nancy J
NJ
Cox
M Eileen
ME
Dolan
Rong Stephanie
RS
Huang
D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D041321:Chromosomes, Human, X / Q000187:drug effects* / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D050172:Genes, X-Linked / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans
D016190:Carboplatin; D002945:Cisplatin
Clin Invest Med. 2003 Oct;26(5):231-42
14596484
Am J Hum Genet. 2007 Mar;80(3):502-9
17273971
Curr Opin Pharmacol. 2002 Aug;2(4):361-5
12127867
Genomics. 1998 Apr 15;49(2):310-3
9598320
Nat Genet. 2007 Feb;39(2):226-31
17206142
Nature. 2005 Oct 27;437(7063):1299-320
16255080
Oncogene. 1997 May 22;14(20):2425-33
9188857
Ann Oncol. 2003 Mar;14(3):449-54
12598352
Nat Genet. 2007 Oct;39(10):1217-24
17873874
Eur J Pharmacol. 2010 Apr 10;631(1-3):1-9
20056115
Biochim Biophys Acta. 2000 Jul 24;1492(2-3):548-52
10899599
Proc Natl Acad Sci U S A. 2010 May 18;107(20):9287-92
20442332
Pharmacogenomics J. 2010 Dec;10(6):505-12
20142840
Am J Hum Genet. 2007 Sep;81(3):427-37
17701890
Bioinformatics. 2010 Jan 15;26(2):259-62
19933162
Am J Hum Genet. 2008 Mar;82(3):631-40
18313023
Pharmacogenet Genomics. 2010 May;20(5):327-37
20393316
J Clin Oncol. 2002 Apr 1;20(7):1932-41
11919254
Science. 2005 Jun 10;308(5728):1572
15947169
Mol Cancer Ther. 2007 Jan;6(1):31-6
17237264
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
12883005