Skip Navigation



Human Molecular Genetics Advance Access published online on April 27, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi170
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Material
Right arrow All Versions of this Article:
14/12/1621    most recent
ddi170v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by French, D.
Right arrow Articles by Relling, M. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by French, D.
Right arrow Articles by Relling, M. V.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved
Received January 5, 2005
Revised April 19, 2005
Accepted April 19, 2005

Article

Global Gene Expression as a Function of Germline Genetic Variation

Deborah French 1, Mark R. Wilkinson 1, Wenjian Yang 1, Luc de Chaisemartin 1, Edwin H. Cook 2, Soma Das 3, Mark J. Ratain 4, William E. Evans 5, James R. Downing 6, Ching-Hon Pui 7, and Mary V. Relling 5*

1 Department of Pharmaceutical Sciences, University of Tennessee, Memphis, TN
2 Department of Psychiatry, University of Chicago, Chicago, IL.; Department of Human Genetics, University of Chicago, Chicago, IL.
3 Department of Human Genetics, University of Chicago, Chicago, IL.
4 Department of Medicine, University of Chicago, Chicago, IL.
5 Department of Pharmaceutical Sciences, University of Tennessee, Memphis, TN; University of Tennessee, Memphis, TN
6 Department of Pathology, University of Tennessee, Memphis, TN
7 Department of Pathology, University of Tennessee, Memphis, TN; Department of Hematology-Oncology, St. Jude Children's Research Hospital, University of Tennessee, Memphis, TN

* To whom correspondence should be addressed.
Mary V. Relling, E-mail: mary.relling{at}stjude.org


  Abstract

Common, functional, germline genetic polymorphisms have been associated with clinical cancer outcomes. There has been little attention to the potential phenotypic consequences of germline genetic variation on downstream genes. We determined the germline status of 16 well-characterized functional polymorphisms in 126 children with newly diagnosed acute lymphoblastic leukemia (ALL). We assessed whether global gene expression profiles of diagnostic ALL blasts from the same patients differed by these germline polymorphic genotypes. Gene expression values were adjusted for ALL-subtype-specific patterns. Of the 16 loci, only the UGT1A1 promoter repeat polymorphism [A(TA)nTAA] (UGT1A1**28) and GSTM1 deletion were significant predictors of global gene expression in a supervised approach that divided patients based on their germline genotypes (UGT1A1: 124 probe sets, false discovery rate [FDR] = 13%%, p = 0.0031; GSTM1: 112 probe sets, FDR = 42.5%%, p = 0.0084). Genes whose expression distinguished the UGT1A1 (TA) 7/7 genotype from the other UGT1A1 genotypes included HDAC1, RELA and SLC2A1; those that distinguished the GSTM1 null genotype from non-null genotype included NBS1 and PRKR. In an unsupervised approach, the gene expression profiles using the entire array delineated two major clusters of patients. The only germline genotype frequency that differed between the two clusters was UGT1A1 (p = 0.002; Fisher's exact test). Although the expression of both GSTM1 and UGT1A1 is limited to specific tissues, both are involved in the conjugation (and thus transport, excretion and lipophilicity) of a broad range of endobiotics and xenobiotics, which could plausibly have consequences for gene expression in different tissues.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
R. S. Huang, P. Chen, S. Wisel, S. Duan, W. Zhang, E. H. Cook, S. Das, N. J. Cox, and M. E. Dolan
Population-specific GSTM1 copy number variation
Hum. Mol. Genet., January 15, 2009; 18(2): 366 - 372.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
C.-H. Pui and W. E. Evans
Treatment of Acute Lymphoblastic Leukemia
N. Engl. J. Med., January 12, 2006; 354(2): 166 - 178.
[Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.