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Human aromatase: gene resequencing and functional genomics
Cynthia X Ma1, Araba A Adjei, Oreste E Salavaggione
1Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Cancer Research
|December 3, 2005
Summary
Genetic variations in the aromatase (CYP19) gene can impact breast cancer treatment. Researchers identified 88 polymorphisms, with some affecting enzyme activity and response to aromatase inhibitors.
Area of Science:
- Genetics
- Biochemistry
- Pharmacology
Background:
- Aromatase (cytochrome P450 19, CYP19) is crucial for estrogen synthesis.
- Aromatase inhibitors are vital in treating estrogen-dependent breast cancer.
Purpose of the Study:
- To identify and characterize genetic polymorphisms in the CYP19 gene.
- To explore the pharmacogenomic implications of these variations for aromatase inhibitor therapy.
Main Methods:
- Resequencing of CYP19 coding and regulatory regions in 240 DNA samples from diverse ethnic groups.
- Functional genomic studies of identified nonsynonymous coding single nucleotide polymorphisms (cSNPs).
Main Results:
- Identified 88 CYP19 polymorphisms, forming 44 haplotypes.
- Four nonsynonymous cSNPs (Trp39Arg, Thr201Met, Arg264Cys, Met364Thr) were functionally assessed.
- Specific variants (Cys264, Thr364, Arg39Cys264) showed reduced enzyme activity and protein levels.
- The double mutant (Arg39Cys264) exhibited altered inhibition constants for exemestane and letrozole.
Conclusions:
- Genetic variations in CYP19 may influence estrogen-dependent diseases.
- CYP19 polymorphisms could contribute to inter-individual variability in response to aromatase inhibitors.