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Polymorphism discovery in 51 chemotherapy pathway genes

Robert R Freimuth1, Ming Xiao, Sharon Marsh

  • 1Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Human Molecular Genetics
|October 22, 2005
PubMed

Insights

Researchers identified genetic variations in genes related to cancer chemotherapy drugs. These genetic polymorphisms may impact treatment effectiveness and toxicity across diverse populations, aiding personalized medicine approaches.

Area of Science:

  • Pharmacogenetics
  • Genomics
  • Cancer Research

Background:

  • Pharmacogenetic studies rapidly assess predictive markers for therapeutic response.
  • Understanding genetic variations is crucial for optimizing cancer chemotherapy.

Purpose of the Study:

  • To identify common genetic polymorphisms in 51 candidate genes involved in antineoplastic agent pathways.
  • To assess the frequency and distribution of these polymorphisms across African-American, Asian-American, and European-American populations.

Main Methods:

  • Resequencing of 51 candidate genes across 120 DNA samples (40 per population group).
  • Genomic sequence analysis covering approximately 378 kb per sample.
  • Comparison of identified variants with public databases and prediction of functional impact using PolyPhen.

Main Results:

  • Identified 904 genetic variants, including 139 coding single nucleotide polymorphisms (cSNPs).
  • Found 40% of polymorphisms were common across all three populations, while 41% were population-specific.
  • 38% of variants were novel, not found in public databases. 35% of non-synonymous cSNPs were predicted as damaging, with frequency decreasing as predicted severity increased.

Conclusions:

  • Provides experimental validation and allele frequencies for polymorphisms in key cancer chemotherapy-related genes.
  • Facilitates the development of pharmacogenetic strategies for personalized cancer treatment.
  • Highlights the importance of population-specific genetic variation in drug response.

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