CYP3A53 and CYP3A41B polymorphisms are associated and more frequent in NSCLC tumors than in normal volunteers

J. M. Kolesar; A. Breunig; J. Miller; P. Stephenson; H. McLeod; S. Marsh; S. Keller; D. Johnson; J. H. Schiller

doi:10.1200/jco.2004.22.14_suppl.2016

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CYP3A53 and CYP3A41B polymorphisms are associated and more frequent in NSCLC tumors than in normal volunteers

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CYP3A53 and CYP3A41B polymorphisms are associated and more frequent in NSCLC tumors than in normal volunteers

J. M. Kolesar, A. Breunig, J. Miller, P. Stephenson, H. McLeod, S. Marsh, S. Keller, D. Johnson and J. H. Schiller

Journal of clinical oncology, Vol.22(14_suppl), pp.2016-2016

07/15/2004

DOI: 10.1200/jco.2004.22.14_suppl.2016

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Abstract

Abstract only Background:. CYP3A4 and CYP3A5 are monooxygenases that metabolize tobacco, endogenous steroids, and numerous anti-cancer agents. The CYP3A4*1B polymorphism leads to increased promotor activity and is associated with small cell lung cancer. The CYP3A5*3 polymorphism causes decreased protein levels and is associated with an increased risk for non small cell lung cancer (NSCLC). Methods: Genomic DNA isolated from primary lung tumor and matched normal nodes from subjects with NSCLC enrolled in E3590 and from peripheral blood mononuclear cells from normal volunteers was evaluated for six CYP3A4/5 polymorphisms by pyrosequencing. Samples were designated as wild-type (WT), heterozygote or homozygous variant for each of the polymorphisms, and differences were evaluated by Chi square analysis and exact binomial confidence intervals were computed for proportions. Results: There were 187 primary tumors with 51 matched nodes and 95 normal volunteers analyzed. Homozygous polymorphisms in CYP3A4/*1B were identified in 2.9% of the tumors, 0.2% of the matched normal nodes and 0% of the normal volunteers. Homozygous polymorphisms in CYP3A5/*3 were identified in 5% of the tumors, 2% of the matched normal nodes and 0% of the normal volunteers. Polymorphisms in CYP3A4/*1B and CYP3A5/*3 were significantly associated (p=0.0001) and both polymorphisms were more common in tumors than in normal volunteers (CI 0.01–0.067 for CYP3A4/*1B, and 0.021–0.105 for CYP3A5/*3). Conclusions: The CYP3A5*3 and 4*1B polymorphisms are associated and occur more frequently in tumors from individuals with NSCLC than in the normal population. Individuals with the CYP3A5*3/4*1B genotype are expected to have high levels of CYP3A4 activity and very little CYP3A5 activity, which may be important in the metabolism of carcinogens such as tobacco smoke and the biotransformation of numerous anti-cancer agents.

Details

Title: Subtitle: CYP3A53 and CYP3A41B polymorphisms are associated and more frequent in NSCLC tumors than in normal volunteers
Creators: J. M. Kolesar - University of Wisconsin–Madison
A. Breunig - University of Wisconsin–Madison
J. Miller - University of Wisconsin–Madison
P. Stephenson - University of Wisconsin–Madison
H. McLeod - Vanderbilt University
S. Marsh - University of Wisconsin–Madison
S. Keller - University of Wisconsin–Madison
D. Johnson - University of Wisconsin–Madison
J. H. Schiller - University of Wisconsin–Madison
Resource Type: Abstract
Publication Details: Journal of clinical oncology, Vol.22(14_suppl), pp.2016-2016
DOI: 10.1200/jco.2004.22.14_suppl.2016
ISSN: 0732-183X
eISSN: 1527-7755
Language: English
Date published: 07/15/2004
Academic Unit: Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984695799802771

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