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Human Molecular Genetics Advance Access published online on October 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi387
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received August 5, 2005
Revised October 3, 2005
Accepted October 11, 2005

Article

Polymorphism discovery in 51 chemotherapy pathway genes

Robert R. Freimuth 1, Ming Xiao 2, Sharon Marsh 3, Matthew Minton 3, Nicholas Addleman 4, Derek J. Van Booven 3, Howard L. McLeod 3, and Pui-Yan Kwok 5*

1 Departments of Medicine, Molecular Biology and Pharmacology, and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
2 Cardiovascular Research Institute and Department of Dermatology, University of California, San Francisco, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
3 Departments of Medicine, Molecular Biology and Pharmacology, and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
4 Cardiovascular Research Institute and Department of Dermatology, University of California, San Francisco, USA
5 Cardiovascular Research Institute and Department of Dermatology, University of California, 513 Parnassus Ave., Box 0793, HSW-901G, San Francisco, CA 94143-0793, USA

* To whom correspondence should be addressed.
Pui-Yan Kwok, E-mail: Kwok{at}ucsf.edu


  Abstract

Candidate gene pharmacogenetic studies offer a strategy for the rapid assessment of putative predictive markers. As a first step toward studying the pharmacogenetics of cancer chemotherapy, 51 candidate genes from the pathways of antineoplastic agents were resequenced to identify common genetic polymorphisms that might alter therapeutic response or toxicity. 40 DNA samples were screened from each of three population groups: African-Americans, Asian-Americans, and European-Americans. Nearly 378 kb of genomic sequence was obtained from each sample. 904 variants were identified, including 139 cSNPs. 356 (40%) of the polymorphisms were common to all three populations and 366 (41%) were population-specific. 346 (38%) of the variants were novel polymorphisms that were not present in the three public databases that were examined. 111 (35%) of the 319 nonsynonymous cSNPs that were identified by either resequencing or database mining were predicted by PolyPhen to be either possibly or probably damaging. For the nonsynonymous cSNPs identified by resequencing, both the number of cSNPs found and the maximum estimated allele frequency decreased with increasing predicted severity. These results provide experimental validation and estimated allele frequencies for polymorphisms in three common ethnic groups, and facilitate applied pharmacogenetic studies of anticancer drugs.


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