Polymorphism discovery in 51 chemotherapy pathway genes

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. Forty 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. Nine hundred and four variants were identified, including 139 coding single nucleotide polymorphisms (cSNPs). Three hundred and fifty-six (40%) polymorphisms were common to all three populations and 366 (41%) were population specific. Three hundred and forty-six (38%) variants were novel polymorphisms that were not present in the three public databases that were examined. One hundred and eleven (35%) of the 319 non-synonymous cSNPs that were identified by either resequencing or database mining were predicted by PolyPhen to be either possibly or probably damaging. For the non-synonymous 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.